Oral pharmaceutical compositions of nicotinamide

ABSTRACT

Described herein are pharmaceutical compositions for the oral administration of nicotinamide, or a combination of nicotinamide and mesalazine, as well as methods of making such pharmaceutical compositions, and therapeutic methods for using them. The compositions comprise delayed-immediate release and delayed-extended release formulation of nicotinamide or a combination of nicotinamide and mesalazine.

RELATED APPLICATIONS

The application claims the priority benefits of U.S. provisionalapplication 62/324,415 filed Apr. 19, 2016, the entire contents of whichare incorporated herein by reference.

FIELD

Described herein are pharmaceutical compositions for the oraladministration of nicotinamide, as well as pharmaceutical compositionsfor the oral administration of nicotinamide and mesalazine, and methodsof making such pharmaceutical compositions, and therapeutic methodsusing them.

BACKGROUND

Nicotinamide (also known as 3-pyridinecarboxamide, niacinamide,nicotinic acid amide, or NAM) is the amide of nicotinic acid (also knownas vitamin B₃ or niacin). Oral dosage forms of nicotinamide are sold asa vitamin/dietary supplement. Various therapeutic uses of orallyadministered nicotinamide have been proposed, including uses as analternative to niacin. WO 2013/186355 describes oral pharmaceuticalcompositions of nicotinamide for influencing the intestinal microbiota.WO 2015/086838 describes oral pharmaceutical compositions ofnicotinamide and mesalazine (also known as 5-amino-2-hydroxybenzoicacid, 5-ASA, or mesalamine) for influencing the intestinal microbiotaand/or treating gastrointestinal inflammation.

However, there remains a need for pharmaceutical compositions for theoral administration of nicotinamide, or a combination of nicotinamideand mesalazine, with different release profiles because patientssuffering from intestinal microbiota and/or gastrointestinalinflammation because gastrointestinal tract symptoms that vary inlocation and degree.

SUMMARY

In one aspect, provided herein is a unit dose pharmaceutical product forthe oral administration of nicotinamide to a subject, comprising (a) aplurality of delayed-immediate release minitablets comprising acompressed matrix comprising nicotinamide provided with a pH-dependententeric coating, wherein the delayed-immediate release minitabletsselectively release nicotinamide in the distal ileum; and (b) aplurality of delayed-extended release minitablets comprising acompressed matrix comprising nicotinamide provided with an innerpH-independent extended release coating and an outer pH-dependententeric coating, wherein the delayed-extended release minitabletsselectively release nicotinamide in the colon, wherein: the relativeamounts of (a) and (b) in the unit dose pharmaceutical product are suchthat from 10 to 90% w/w of the nicotinamide provided in the unit dosepharmaceutical is present in the delayed-extended release minitablets of(b), and the total amount of nicotinamide in the unit dosepharmaceutical product is from about 0.25 to about 6 g.

In some embodiments, the delayed-immediate release minitablets releasenicotinamide at a pH of 5.5 or greater. In some embodiments, whensubject to in vitro dissolution testing according to USP Type 1 Basketat 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7 buffer,the delayed-immediate release minitablets exhibit release of less than10% of their total nicotinamide content at pH 1.2 and pH 4.5, andexhibit release of substantially all of their total nicotinamide contentwithin 60 minutes at pH 7. In some embodiments, when subject to in vitrodissolution testing according to USP Type 1 Basket at 37° C. and 100 rpmin 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed bypH 4.5 buffer for 2 hours, followed by pH 7 buffer, thedelayed-immediate release minitablets exhibit release of less than 10%of their total nicotinamide content at pH 1.2 and pH 4.5, and exhibitrelease of substantially all of their total nicotinamide content within30 minutes at pH 7.

In some embodiments, wherein the delayed-immediate release minitabletsof (a) release at least 50% w/w of their total nicotinamide content inthe distal ileum. In some embodiments, the delayed-immediate releaseminitablets of (a) release at least 70% w/w of their total nicotinamidecontent in the distal ileum. In some embodiments, the delayed-immediaterelease minitablets of (a) release at least 30% w/w of their totalnicotinamide content in the distal ileum.

In some embodiments, the delayed-extended release minitablets releasenicotinamide at a pH of 7 or greater. In some embodiments, when subjectto in vitro dissolution testing according to USP Type 1 Basket at 37° C.and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours,followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12hours, the delayed-extended release minitablets exhibit substantially norelease of nicotinamide at pH 1.2 and pH 4.5, and exhibit extendedrelease of nicotinamide over at least 4 hours at pH 7.0. In someembodiments, when subject to in vitro dissolution testing according toUSP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium ofpH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours,followed by pH 7.0 buffer for 12 hours, the delayed-extended releaseminitablets exhibit substantially no release of nicotinamide at pH 1.2and pH 4.5, and exhibit extended release of nicotinamide over at least8-12 hours at pH 7.0.

In some embodiments, the delayed-extended release minitablets of (b)release at least 50% w/w of their total nicotinamide content in thecolon. In some embodiments, the delayed-extended release minitablets of(b) release at least 70% w/w of their total nicotinamide content in thecolon.

In some embodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets comprises 20-50% w/w of (a), based on the totalweight of (a) and (b). In some embodiments, the unit dose pharmaceuticalproduct comprising nicotinamide minitablets comprises 30-60% w/w of (a),based on the total weight of (a) and (b). In some embodiments, the unitdose pharmaceutical product comprising nicotinamide minitabletscomprises 50-80% of (a), based on the total weight of (a) and (b). Insome embodiments, the unit dose pharmaceutical product comprisingnicotinamide tablets comprises at least 50% w/w of (a) based on thetotal weight of (a) and (b). In some embodiments, the unit dosepharmaceutical product comprising nicotinamide minitablets comprises atleast 60% w/w of (a) based on the total weight of (a) and (b). In someembodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets comprises at least 70% w/w of (a) based on thetotal weight of (a) and (b). In some embodiments, the unit dosepharmaceutical product comprising nicotinamide minitablets comprises atleast 80% w/w of (a) based on the total weight of (a) and (b). In someembodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets comprises at least 90% w/w of (a) based on thetotal weight of (a) and (b). In some embodiments, the unit dosepharmaceutical product comprising nicotinamide minitablets comprisesgreater than 50% w/w of (b), based on the total weight of (a) and (b).In some embodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets comprises less than 50 w/w of (b), based on thetotal weight of (a) and (b).

In some embodiments, when subject to in vitro dissolution testingaccording to USP Apparatus 2 at 37° C. and 100 rpm in 750 mL of 0.1N HCLfor 2 hours, followed by 1000 mL of pH 7 phosphate buffer for 12 hours,the unit dose pharmaceutical product comprising nicotinamide minitabletsexhibits release of nicotinamide of ≤10% at 2 hours, 60-90% at 6 hours,and ≥90% at 14 hours.

In some embodiments, the relative amounts of (a) and (b) in the unitdose pharmaceutical product comprising nicotinamide tablets are suchthat at least 50% w/w of the nicotinamide provided in the unit dosepharmaceutical product comprising nicotinamide minitablets is present inthe delayed-extended release minitablets (b). In some embodiments, therelative amounts of (a) and (b) in the unit dose pharmaceutical productcomprising nicotinamide minitablets are such that at least 60% w/w ofthe nicotinamide provided in the unit dose pharmaceutical productcomprising nicotinamide minitablets is present in the delayed-extendedrelease minitablets (b). In some embodiments, the relative amounts of(a) and (b) in the unit dose pharmaceutical product comprisingnicotinamide minitablets are such that at least 65% w/w of thenicotinamide provided in the unit dose pharmaceutical product comprisingnicotinamide minitablets is present in the delayed-extended releaseminitablets (b). In some embodiments, the relative amounts of (a) and(b) in the unit dose pharmaceutical product comprising nicotinamideminitablets are such that at least 70% w/w of the nicotinamide providedin the unit dose pharmaceutical product comprising nicotinamideminitablets is present in the delayed-extended release minitablets (b).In some embodiments, the relative amounts of (a) and (b) in the unitdose pharmaceutical product comprising nicotinamide minitablets are suchthat at least 75% w/w of the nicotinamide provided in the unit dosepharmaceutical product comprising nicotinamide minitablets is present inthe delayed-extended release minitablets (b). In some embodiments, therelative amounts of (a) and (b) in the unit dose pharmaceutical productcomprising nicotinamide minitablets are such that at least 80% w/w ofthe nicotinamide provided in the unit dose pharmaceutical productcomprising nicotinamide minitablets is present in the delayed-extendedrelease minitablets (b). In some embodiments, the relative amounts of(a) and (b) in the unit dose pharmaceutical product comprisingnicotinamide minitablets are such that at least 85% w/w of thenicotinamide provided in the unit dose pharmaceutical product comprisingnicotinamide minitablets is present in the delayed-extended releaseminitablets (b). In some embodiments, the relative amounts of (a) and(b) in the unit dose pharmaceutical product comprising nicotinamideminitablets are such that at least 90% w/w of the nicotinamide providedin the unit dose pharmaceutical product comprising nicotinamideminitablets is present in the delayed-extended release minitablets (b).

In some embodiments, the total amount of nicotinamide in the unit dosepharmaceutical product comprising nicotinamide minitablets is from 0.25g to 6 g. In some embodiments, the total amount of nicotinamide in theunit dose pharmaceutical product comprising nicotinamide minitablets isfrom 2 to 3 g.

In some embodiments, the compressed matrix of (a) and the compressedmatrix of (b) comprise nicotinamide and a pharmaceutically acceptablebinder. In some embodiments, the compressed matrix of (a) and thecompressed matrix of (b) comprise at least 60% w/w nicotinamide. In someembodiments, the compressed matrix of (a) and the compressed matrix of(b) comprise at least 70% w/w nicotinamide. In some embodiments, thecompressed matrix of (a) and the compressed matrix of (b) comprise atleast 80% w/w nicotinamide. In some embodiments, the compressed matrixof (a) and the compressed matrix of (b) comprise at least 90% w/wnicotinamide. In some embodiments, the compressed matrix of (a) and thecompressed matrix of (b) comprise nicotinamide and hydroxylpropylcellulose. In some embodiments, the compressed matrix of (a) and thecompressed matrix of (b) comprise nicotinamide, a pharmaceuticallyacceptable binder, a pharmaceutically acceptable filler, and apharmaceutically acceptable lubricant. In some embodiments, thecompressed matrix of (a) and the compressed matrix of (b) comprisenicotinamide, hydroxylpropyl cellulose, microcrystalline cellulose, andmagnesium stearate. In some embodiments, the pH-dependent entericcoating of (a) comprises one or more polymers selected from the groupconsisting of poly[methacrylic acid-co-ethyl acrylate (1:1)],hypromellose acetate succinate, and hypromellose phthalate. In someembodiments, the pH-dependent enteric coating of (b) comprises one ormore polymers selected from the group consisting of poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) [7:3:1],methacrylic acid and methyl methacrylate copolymer (1:2), andhypromellose acetate succinate. In some embodiments, the pH-independentextended release coating of (b) comprises a pH-independent extendedrelease polymer and a pore-forming agent. In some embodiments, thepH-independent extended release coating of (b) comprises ethyl celluloseand a pore-forming agent. In some embodiments, the pH-independentextended release coating of (b) comprises ethyl cellulose andhydroxypropyl methylcellulose.

In some embodiments, the minitablets of (a) and/or the minitablets of(b) further comprise a seal coat exterior to the pH-dependent entericcoating.

In some embodiments, the minitablets of (a) and the minitablets of (b)have a longest diameter of 1-4 mm.

In some embodiments, the minitablets of (a) and the minitablets of (b)are provided in a sachet, capsule, or vial.

In another aspect, provided herein is a method of administeringnicotinamide to a subject in need thereof, or for treating inflammatorybowel disease, such as ulcerative colitis and mild-to-moderate Crohn'sdisease, comprising orally administering to the subject a unit dosepharmaceutical product comprising nicotinamide minitablets as describedherein.

In another aspect, provided herein is the use of nicotinamide in thepreparation of a medicament for orally administering nicotinamide to asubject in need thereof, or for treating inflammatory bowel disease,such as ulcerative colitis and mild-to-moderate Crohn's disease, whereinthe medicament comprises a unit dose pharmaceutical product comprisingnicotinamide minitablets as described herein.

In another aspect, provided herein is a unit dose pharmaceutical productcomprising nicotinamide as described herein for orally administeringnicotinamide to a subject in need thereof, or for treating inflammatorybowel disease, such as ulcerative colitis and mild-to-moderate Crohn'sdisease.

In another aspect, provided herein is a unit dose pharmaceutical productfor the oral administration of nicotinamide and mesalazine to a subject,comprising (a) a plurality of delayed-immediate release minitabletscomprising a compressed matrix comprising nicotinamide provided with apH-dependent enteric coating, wherein the delayed-immediate releaseminitablets selectively release nicotinamide in the distal ileum; (b) aplurality of delayed-extended release minitablets comprising acompressed matrix comprising nicotinamide provided with an innerpH-independent extended release coating and an outer pH-dependententeric coating, wherein the delayed-extended release minitabletsselectively release nicotinamide in the colon; (c) a plurality ofdelayed-immediate release minitablets comprising a compressed matrixcomprising mesalazine provided with a pH-dependent enteric coating,wherein the delayed-immediate release minitablets selectively releasemesalazine in the distal ileum; and (d) a plurality of delayed-extendedrelease minitablets comprising a compressed matrix comprising mesalazineprovided with an inner pH-independent extended release coating and anouter pH-dependent enteric coating, wherein the delayed-extended releaseminitablets selectively release mesalazine in the colon, wherein: therelative amounts of (a) and (b) in the unit dose pharmaceutical productare such that from 10 to 90% w/w of the nicotinamide provided in theunit dose pharmaceutical is present in the delayed-extended releaseminitablets of (b), the relative amounts of (c) and (d) in the unit dosepharmaceutical product are such that from 10 to 90% w/w of themesalazine provided in the unit dose pharmaceutical is present in thedelayed-extended release minitablets of (d), wherein the relativeamounts of (a) and (b) may be selected independently of the relativeamounts of (c) and (d) and the relative amounts of (c) and (d) may beselected independently of the relative amounts of (a) and (b), the totalamount of nicotinamide in the unit dose pharmaceutical product is fromabout 0.25 to about 4 g and the total amount of mesalazine in the unitdose pharmaceutical product is from about 0.4 to about 6 g.

In some embodiments, the delayed-immediate release minitablets releasenicotinamide or mesalazine at a pH of 5.5 or greater. In someembodiments, when subject to in vitro dissolution testing according toUSP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium ofpH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours,followed by pH 7 buffer, the delayed-immediate release minitablets (a)comprising nicotinamide exhibit release of less than 10% of their totalnicotinamide content at pH 1.2 and pH 4.5, and exhibit release ofsubstantially all of their total nicotinamide content within 60 minutesat pH 7. In some embodiments, when subject to in vitro dissolutiontesting according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7 buffer, the delayed-immediaterelease minitablets (a) comprising nicotinamide exhibit release of lessthan 10% of their total nicotinamide content at pH 1.2 and pH 4.5, andexhibit release of substantially all of their total nicotinamide contentwithin 30 minutes at pH 7. In some embodiments, when subject to in vitrodissolution testing according to USP Type 1 Basket at 37° C. and 100 rpmin 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed bypH 4.5 buffer for 2 hours, followed by pH 7 buffer, thedelayed-immediate release minitablets (c) comprising mesalazine exhibitsubstantially no release of mesalazine at pH 1.2 and pH 4.5, and releasesubstantially all mesalazine within 120 minutes at pH 7. In someembodiments, when subject to in vitro dissolution testing according toUSP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium ofpH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours,followed by pH 7 buffer for 2 hours, the delayed-immediate releaseminitablets (c) comprising mesalazine exhibit substantially no releaseof mesalazine at pH 1.2 and pH 4.5, and release substantially allmesalazine within 90 minutes at pH 7.

In some embodiments, the delayed-immediate release minitablets of (a)release at least 50% w/w of their total nicotinamide content in thedistal ileum and/or wherein the delayed-immediate release minitablets of(c) release at least 50% w/w of their total mesalazine content in thedistal ileum. In some embodiments, the delayed-immediate releaseminitablets of (a) release at least 70% w/w of their total nicotinamidecontent in the distal ileum and/or wherein the delayed-immediate releaseminitablets of (c) release at least 70% w/w of their total mesalazinecontent in the distal ileum.

In some embodiments, the delayed-extended release minitablets releasenicotinamide or mesalazine at a pH of 7 or greater. In some embodiments,when subject to in vitro dissolution testing according to USP Type 1Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed bypH 7.0 buffer for 12 hours, the delayed-extended release minitablets (b)comprising nicotinamide exhibit substantially no release of nicotinamideat pH 1.2 and pH 4.5, and exhibit extended release of nicotinamide overat least 4 hours at pH 7.0. In some embodiments, when subject to invitro dissolution testing according to USP Type 1 Basket at 37° C. and100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours,followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12hours, the delayed-extended release minitablets (b) comprisingnicotinamide exhibit substantially no release of nicotinamide at pH 1.2and pH 4.5, and exhibit extended release of nicotinamide over at least8-12 hours at pH 7.0. In some embodiments, when subject to in vitrodissolution testing according to USP Type 1 Basket at 37° C. and 100 rpmin 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed bypH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, thedelayed-extended release minitablets (d) comprising mesalazine exhibitsubstantially no release of mesalazine at pH 1.2 and pH 4.5, and exhibitextended release of mesalazine over at least 4 hours at pH 7.0. In someembodiments, when subject to in vitro dissolution testing according toUSP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium ofpH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours,followed by pH 7.0 buffer for 12 hours, the delayed-extended releaseminitablets exhibit substantially no release of mesalazine at pH 1.2 andpH 4.5, and exhibit extended release of mesalazine over at least 6 hoursat pH 7.0. In some embodiments, when subject to in vitro dissolutiontesting according to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, thedelayed-extended release minitablets exhibit substantially no release ofmesalazine at pH 1.2 and pH 4.5, and exhibit extended release ofmesalazine over at least 8 hours at pH 7.0. In some embodiments, whensubject to in vitro dissolution testing according to USP Type 1 Basketat 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7.0buffer for 12 hours, the delayed-extended release minitablets (d)comprising mesalazine exhibit substantially no release of mesalazine atpH 1.2 and pH 4.5, and exhibit extended release of mesalazine over 12hours at pH 7.0.

In some embodiments, the delayed-extended release minitablets of (b)release at least 50% w/w of their total nicotinamide content in thecolon and/or wherein the delayed-extended release minitablets of (d)release at least 50% w/w of their total mesalazine content in the colon.In some embodiments, the delayed-extended release minitablets of (b)release at least 70% w/w of their total nicotinamide content in thecolon and/or wherein the delayed-extended release minitablets of (d)release at least 70% w/w of their total mesalazine content in the colon.

In some embodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets comprises 20-50% w/wof (a) based on the total weight of (a) and (b). In some embodiments,the unit dose pharmaceutical product comprising nicotinamide minitabletsand mesalazine minitablets comprises 30-60% w/w of (a) based on thetotal weight of (a) and (b). In some embodiments, the unit dosepharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets comprises 50-80% w/w of (a) based on the totalweight of (a) and (b). In some embodiments, the unit dose pharmaceuticalproduct comprising nicotinamide minitablets and mesalazine minitabletscomprises at least 50% w/w of (a) based on the total weight of (a) and(b). In some embodiments, the unit dose pharmaceutical productcomprising nicotinamide minitablets and mesalazine minitablets comprisesat least 60% w/w of (a) based on the total weight of (a) and (b). Insome embodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets comprises at least70% w/w of (a) based on the total weight of (a) and (b). In someembodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets comprises at least80% w/w of (a) based on the total weight of (a) and (b). In someembodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets comprises at least90% w/w of (a) based on the total weight of (a) and (b).

In some embodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets comprises greaterthan 50 w/w of (b), based on the total weight of (a) and (b). In someembodiments, the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets comprises less than50% w/w of (b), based on the total weight of (a) and (b).

In some embodiments, at least 60% w/w of the mesalazine provided in theunit dose pharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets is present in (d) based on the total weight of(c) and (d). In some embodiments, at least 65 w/w of the mesalazineprovided in the unit dose pharmaceutical product comprising nicotinamideminitablets and mesalazine minitablets is present in (d) based on thetotal weight of (c) and (d). In some embodiments, at least 70% w/w ofthe mesalazine provided in the unit dose pharmaceutical productcomprising nicotinamide minitablets and mesalazine minitablets ispresent in (d) based on the total weight of (c) and (d). In someembodiments, at least 75% w/w of the mesalazine provided in the unitdose pharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets is present in (d) based on the total weight of(c) and (d). In some embodiments, at least 80% w/w of the mesalazineprovided in the unit dose pharmaceutical product comprising nicotinamideminitablets and mesalazine minitablets is present in (d) based on thetotal weight of (c) and (d). In some embodiments, at least 85% w/w ofthe mesalazine provided in the unit dose pharmaceutical productcomprising nicotinamide minitablets and mesalazine minitablets ispresent in (d) based on the total weight of (c) and (d). In someembodiments, at least 90% w/w of the mesalazine provided in the unitdose pharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets is present in (d) based on the total weight of(c) and (d).

In some embodiments, when subject to in vitro dissolution testingaccording to USP Apparatus 2 at 37° C. and 100 rpm in 750 mL of 0.1N HCLfor 2 hours, followed by 1000 mL of pH 7 phosphate buffer for 12 hours,the unit dose pharmaceutical product comprising nicotinamide minitabletsand mesalazine minitablets exhibits release of nicotinamide of ≤10% at 2hours, 60-90% at 6 hours, and ≥90% at 14 hours. In some embodiments,when subject to in vitro dissolution testing according to USP Apparatus2 at 37° C. and 100 rpm in 750 mL of 0.1N HCL for 2 hours, followed by1000 mL of pH 7 phosphate buffer for 12 hours, the unit dosepharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets exhibits release of mesalazine of ≤10% at 2hours, 45-75% at 6 hours, and ≥90% at 14 hours.

In some embodiments, the total amount of nicotinamide in the unit dosepharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets is from 0.25 to 4 g and the total amount ofmesalazine in the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets is from 0.4 to 6 g.In some embodiments, the total amount of nicotinamide in the unit dosepharmaceutical product comprising nicotinamide minitablets andmesalazine minitablets is from 2 to 3 g and the total amount ofmesalazine in the unit dose pharmaceutical product comprisingnicotinamide minitablets and mesalazine minitablets is 2 g or 4 g.

In some embodiments, the compressed matrix of (c) and the compressedmatrix of (d) comprise micronized mesalazine. In some embodiments, themicronized mesalazine has a particle size distribution such that the90^(th) percentile, D(v, 0.9), is no more than 30 μm. In someembodiments, the micronized mesalazine has a particle size distributionsuch that a typical value D(v,0.9) is 16-17 μm.

In some embodiments, the mesalazine has a particle size distributionsuch that the 90^(th) percentile is no more than 100 μm. In someembodiments, the mesalazine has a particle size distribution such that atypical value D(v,0.9) is 40-50 μm.

In some embodiments, the compressed matrix of (a) and the compressedmatrix of (b) comprise nicotinamide and a pharmaceutically acceptablebinder. In some embodiments, the compressed matrix of (a) and thecompressed matrix of (b) comprise nicotinamide and hydroxypropylcellulose. In some embodiments, the compressed matrix of (c) and thecompressed matrix of (d) comprise mesalazine and a pharmaceuticallyacceptable binder. In some embodiments, the compressed matrix of (c) andthe compressed matrix of (d) comprise mesalazine and povidone.

In some embodiments, the compressed matrix of (a) and the compressedmatrix of (b) comprise nicotinamide, a pharmaceutically acceptablebinder, a pharmaceutically acceptable filler, a pharmaceuticallyacceptable lubricant, and a pharmaceutically acceptable plasticizer. Insome embodiments, the compressed matrix of (a) and the compressed matrixof (b) comprise nicotinamide, hydroxylpropyl cellulose, microcrystallinecellulose, and magnesium stearate.

In some embodiments, the compressed matrix of (c) and the compressedmatrix of (d) comprise mesalazine, a pharmaceutically acceptable binder,a pharmaceutically acceptable filler, and a pharmaceutically acceptablelubricant. In some embodiments, the compressed matrix of (c) and thecompressed matrix of (d) comprise mesalazine, povidone, microcrystallinecellulose, and magnesium stearate. In some embodiments, the pH-dependententeric coating of (a) and (c) comprise one or more polymers selectedfrom the group consisting of poly[methacrylic acid-co-ethyl acrylate(1:1)], hypromellose acetate succinate, and hypromellose phthalate.

In some embodiments, the pH-dependent enteric coating of (b) and (d)comprise one or more polymers selected from the group consisting ofpoly[methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1],methacrylic acid and ethyl acrylate copolymer (1:1) and hypromelloseacetate succinate. In some embodiments, the pH-independent extendedrelease coating of (b) and (d) comprise a pH-independent extendedrelease polymer and a pore-forming agent. In some embodiments, thepH-independent extended release coating of (b) and (d) comprise ethylcellulose and a pore-forming agent. In some embodiments, thepH-independent extended release coating of (b) and (d) comprise ethylcellulose and hydroxypropyl methylcellulose.

In some embodiments, the minitablets of (a), the minitablets of (b), theminitablets of (c), and/or the minitablets of (d) further comprise aseal coat exterior to the pH-dependent enteric coating.

In some embodiments, the minitablets of (a), the minitablets of (b), theminitablets of (c), and/or the minitablets of (d) have a longestdiameter of 1-3 mm.

In some embodiments, the minitablets of (a), the minitablets of (b), theminitablets of (c), and/or the minitablets of (d) are provided in asachet, capsule, or vial.

In another aspect, provided herein is a method of administeringnicotinamide and/or mesalazine to a subject in need thereof, or fortreating inflammatory bowel disease, such as ulcerative colitis andmild-to-moderate Crohn's disease, comprising orally administering to thesubject a unit dose pharmaceutical product comprising nicotinamideminitablets and mesalazine minitablets as described herein.

In another aspect, provided herein is the use of nicotinamide andmesalazine in the preparation of a medicament for orally administeringnicotinamide and mesalazine to a subject in need thereof, or fortreating inflammatory bowel disease, such as ulcerative colitis andmild-to-moderate Crohn's disease, wherein the medicament comprises aunit dose pharmaceutical product comprising nicotinamide and mesalazineminitablets as described herein.

In another aspect, provided herein is a unit dose pharmaceutical productcomprising nicotinamide and mesalazine as described herein for orallyadministering nicotinamide and mesalainze to a subject in need thereof,or for treating inflammatory bowel disease, such as ulcerative colitisand mild-to-moderate Crohn's disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart illustrating the manufacturing process for a unitdose pharmaceutical product of nicotinamide as described herein.

FIG. 2 is a general flow chart illustrating the manufacturing processfor a unit dose pharmaceutical product of mesalazine as describedherein.

FIG. 3 is a flow chart illustrating the manufacturing process for a unitdose pharmaceutical product of mesalazine as described herein.

FIG. 4 is a graphical depiction of the dissolution profile ofdelayed-immediate release minitablets comprising nicotinamide asdescribed herein.

FIG. 5 is a graphical depiction of the dissolution profile ofdelayed-immediate release minitablets comprising nicotinamide asdescribed herein.

FIG. 6 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising nicotinamide asdescribed herein.

FIG. 7 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising nicotinamide asdescribed herein.

FIG. 8 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising nicotinamide asdescribed herein.

FIG. 9 is a graphical depiction of the dissolution profile of acombination product comprising delayed-immediate release anddelayed-extended release (30:70) minitablets comprising nicotinamide asdescribed herein.

FIG. 10 is a graphical depiction of the dissolution profile of acombination product comprising delayed-immediate release anddelayed-extended release (50:50) minitablets comprising nicotinamide asdescribed herein.

FIG. 11 is a graphical depiction of the dissolution profile ofdelayed-immediate release minitablets comprising mesalazine as describedherein.

FIG. 12 is a graphical depiction of the dissolution profile ofdelayed-immediate release minitablets comprising mesalazine as describedherein.

FIG. 13 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising mesalazine as describedherein.

FIG. 14 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising mesalazine as describedherein.

FIG. 15 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising mesalazine as describedherein.

FIG. 16 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising mesalazine as describedherein.

FIG. 17 is a graphical depiction of the dissolution profile ofdelayed-extended release minitablets comprising mesalazine as describedherein.

FIG. 18 is a graphical depiction of the dissolution profile of acombination product comprising delayed-immediate release anddelayed-extended release (30:70) minitablets comprising mesalazine asdescribed herein.

FIG. 19 is a graphical depiction of the dissolution profile of acombination product comprising delayed-immediate release anddelayed-extended release (50:50) minitablets comprising mesalazine asdescribed herein.

FIG. 20 is a graphical depiction of the dissolution profile of acombination product comprising delayed-extended release anddelayed-immediate release minitablets comprising mesalazine as describedherein.

FIG. 21 is a graphical depiction of the dissolution profile of acombination product comprising delayed-extended release anddelayed-immediate release minitablets comprising mesalazine as describedherein.

DETAILED DESCRIPTION

Described herein are pharmaceutical compositions for the oraladministration of nicotinamide, or a combination of nicotinamide andmesalazine, methods of making such pharmaceutical compositions, andtherapeutic methods for using them. In accordance with some embodiments,the compositions deliver nicotinamide and/or mesalazine to the lowergastrointestinal tract, such as the distal ileum and/or the colon, overa period of time sufficient to achieve therapeutic effect.

In accordance with some embodiments, there are provided compositionscomprising (a) a plurality of delayed-immediate release minitabletscomprising nicotinamide that selectively release nicotinamide in thedistal ileum and (b) a plurality of delayed-extended release minitabletscomprising nicotinamide that selectively release nicotinamide in thecolon. In some embodiments, the compositions are provided in the form ofunit dose pharmaceutical products comprising (a) a plurality ofdelayed-immediate release minitablets comprising nicotinamide thatselectively release nicotinamide in the distal ileum and (b) a pluralityof delayed-extended release minitablets comprising nicotinamide thatselectively release nicotinamide in the colon.

In accordance with some embodiments, there are provided compositionscomprising (a) a plurality of delayed-immediate release minitabletscomprising nicotinamide that selectively release nicotinamide in thedistal ileum, (b) a plurality of delayed-extended release minitabletscomprising nicotinamide that selectively release nicotinamide in thecolon, (c) a plurality of delayed-immediate release minitabletscomprising mesalazine that selectively release mesalazine in the distalileum, and (d) a plurality of delayed-extended release minitabletscomprising mesalazine that selectively release mesalazine in the colon.In some embodiments, the compositions are provided in the form of unitdose pharmaceutical products comprising (a) a plurality ofdelayed-immediate release minitablets comprising nicotinamide thatselectively release nicotinamide in the distal ileum, (b) a plurality ofdelayed-extended release minitablets comprising nicotinamide thatselectively release nicotinamide in the colon, (c) a plurality ofdelayed-immediate release minitablets comprising mesalazine thatselectively release mesalazine in the distal ileum, and (d) a pluralityof delayed-extended release minitablets comprising mesalazine thatselectively release mesalazine in the colon.

Definitions

Technical and scientific terms used herein have the meanings commonlyunderstood by one of ordinary skill in the art of pharmaceuticalformulations to which the present disclosure pertains, unless otherwisedefined. Reference is made herein to various methodologies known tothose of ordinary skill in the art. Suitable materials and/or methodsknown to those of ordinary skill in the art can be utilized in carryingout the present disclosure. However, specific materials and methods aredescribed. Materials, reagents and the like to which reference is madein the following description and examples are obtainable from commercialsources, unless otherwise noted.

As used herein, the singular forms “a,” “an,” and “the” designate boththe singular and the plural, unless expressly stated to designate thesingular only.

As used herein, the term “about” means that the number or range is notlimited to the exact number or range set forth, but encompass valuesaround the recited number or range as will be understood by persons ofordinary skill in the art depending on the context in which the numberor range is used. Unless otherwise apparent from the context orconvention in the art, “about” means up to plus or minus 10% of theparticular term.

As used herein, “subject” denotes any mammal, including humans. Forexample, a subject may be suffering from or at risk of developing acondition that can be diagnosed, treated or prevented with nicotinamideor a combination of nicotinamide and mesalazine, or may be takingnicotinamide or a combination of nicotinamide and mesalazine for otherpurposes.

The terms “administer,” “administration,” or “administering” as usedherein refer to (1) providing, giving, dosing and/or prescribing, suchas by either a health professional or his or her authorized agent orunder his direction, and (2) putting into, taking or consuming, such asby a health professional or the subject.

The terms “treat”, “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition or one ormore symptoms thereof, whether or not the disease or condition isconsidered to be “cured” or “healed” and whether or not all symptoms areresolved. The terms also include reducing or preventing progression of adisease or condition or one or more symptoms thereof, impeding orpreventing an underlying mechanism of a disease or condition or one ormore symptoms thereof, and achieving any therapeutic and/or prophylacticbenefit.

As used herein, the phrase “therapeutically effective amount” refers toa dose that provides the specific pharmacological effect for which thedrug is administered in a subject in need of such treatment. It isemphasized that a therapeutically effective amount will not always beeffective in treating the conditions described herein, even though suchdose is deemed to be a therapeutically effective amount by those ofskill in the art. For convenience only, exemplary doses andtherapeutically effective amounts are provided below with reference toadult human subjects. Those skilled in the art can adjust such amountsin accordance with standard practices as needed to treat a specificsubject and/or condition/disease.

As used herein, a composition that “selectively releases” an activeagent (e.g. nicotinamide or mesalazine) in a specific region of thedigestive tract (e.g., the distal ileum or colon) refers to acomposition that, after oral administration, releases most of its activeagent in that region, such as by not releasing more than 25%, w/w morethan 30% w/w, more than about 40% w/w, or more than about 50% w/w of thetotal amount of active agent until the composition reaches that specificregion of the digestive tract, and/or such as by releasing more thanabout 50% w/w, more than about 60% w/w, or more than about 75% w/w ofthe total amount of active agent in the composition in that region ofthe digestive tract. A composition that “selectively releases” an activeagent in a specific region of the digestive tract may exhibit release ofactive agent higher (earlier) in the digestive tract, lower (later) inthe digestive tract, or both.

As used herein, the term “nicotinamide” includes nicotinamide andpharmaceutically acceptable salts thereof. In contrast, the terms“3-pyridinecarboxamide”, “niacinamide”, and “nicotinic acid amide” areused to refer to nicotinamide specifically, as distinguished frompharmaceutically acceptable salts thereof.

As used herein, the term “mesalazine” includes mesalazine (also known as“mesalamine”) and pharmaceutically acceptable salts and esters thereof.In contrast, the terms “5-aminosalicylic acid”, and “5-ASA” are used torefer to mesalazine specifically, as distinguished from pharmaceuticallyacceptable salts and esters thereof.

As used herein, the term “minitablets” refers to a solid form preparedby compression of the active ingredient (e.g., nicotinamide ormesalazine) with one or more pharmaceutically acceptable excipients(including but not limited to, fillers, binders, lubricants, and thelike), typically by using a tableting machine (such as a rotary tabletpress) that produces smooth tablets of uniform shape and size.Minitablets typically have a size ranging from about 1 mm to about 3 mmin diameter, and optionally may be provided with one or morepharmaceutically acceptable coatings.

Therapeutic Agents

Nicotinamide

As noted above, the compositions described herein include nicotinamide(or a pharmaceutically acceptable salt thereof). Nicotinamide is alsoknown as 3-pyridinecarboxamide, niacinamide, and nicotinic acid amide,and has the molecular formula C₆H₆N₂O and a molecular weight of 122.13.It is registered under CAS Registry Number 98-92-0 and Einecs 202-713-4.

Mesalazine

As noted above, the compositions described herein may include mesalazine(or a pharmaceutically acceptable salt or ester thereof). Mesalazine isalso known as 5-aminosalicylic acid, 2-hydroxy 5-aminobenzoic acid,3-carboxy-4-hydroxyaniline, mesalamine, and 5-amino-2-hydroxybenzoicacid, and has the molecular formula C₇H₇NO₃ and a molecular weight of153.14. It is registered under CAS Registry Number 89-57-6 and Einecs201-919-1.

Exemplary pharmaceutically acceptable salts include acid addition salts,such as hydrochloride salts. Any pharmaceutically acceptable salt can beused, such as sodium and calcium salts. Other non-limiting exemplarysalts include salts formed with a carboxylic acid group, alkali metalsalts, and alkaline earth metal salts. Non-limiting examples ofpharmaceutically acceptable esters include straight chain or branchedC₁-C₁₈ alkyl esters, including methyl, ethyl, propyl, isopropyl, butyl,isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl,cetyl, and stearyl, and the like; straight chain or branched C₂-C₁₈alkenyl esters, including vinyl, allyl, undecenyl, oleyl, linolenyl, andthe like; C₃-C₈ cycloalkyl esters, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and the like; arylesters, including phenyl, toluoyl, xylyl, naphthyl, and the like;alicyclic esters, including menthyl and the like; or aralkyl esters,including benzyl, phenethyl, and the like.

The compositions and unit dose pharmaceutical products described hereinmay include a therapeutically effective amount of nicotinamide, or atherapeutically effective amount of one or both of nicotinamide andmesalazine, or a therapeutically effective amount of a combination ofnicotinamide and mesalazine. The therapeutically effective amount(s) maydepend on the subject being treated, the condition being treated, thedesired effect, and the intended duration of therapeutic effect of thecompositions and products.

A therapeutically effective amount of orally administered nicotinamidefor influencing the gastrointestinal microbiota and/or for treatinggastrointestinal inflammation, including inflammatory bowel disease mayvary for a given subject, category of subjects, or condition beingtreated. In some embodiments, a therapeutically effective amount oforally administered nicotinamide for influencing the gastrointestinalmicrobiota and/or for treating gastrointestinal inflammation is about 2to 3 g/day for an adult human subject, optionally administered individed two to four doses (e.g., 1 g two times a day, 0.5 g four times aday, etc.). Thus, a unit dose pharmaceutical product as described hereinmay include from about 0.25 g to about 6 g nicotinamide per unit dose,including about 0.25 g, about 0.5 g, about 0.75 g, about 1 g, about 1.25g, about 1.5 g, about 1.75 g, about 2 g, about 2.5 g, about 3 g, about3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, or about 6 g,such as 0.25 g, 0.5 g, 0.75 g, 1 g, 1.25 g, 1.5 g, 1.75 g, 2 g, 2.5 g, 3g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, or 6 g, and amounts between any ofthese values. In some embodiments, the amount of nicotinamide iseffective to modulates gastrointestinal microbiota and thereby exert atherapeutic effect in inflammatory bowel conditions where microbiotaplay a pathogenic role, such as ulcerative colitis and Crohn's disease.

A therapeutically effective amount of orally administered mesalazine forthe treatment of gastrointestinal inflammation including inflammatorybowel disease is generally about 2 to about 6 g/day for an adult humansubject, optionally administered in divided two to four doses (e.g.,about 4 g once a day, about 2 g two times a day, about 1 g four times aday, etc.). For example, therapeutic doses of mesalazine for patientswith active ulcerative colitis of any disease extent beyond proctitis istypically from about 2 to about 5 g a day, including from about 2.4 toabout 4.8 g/day, with or without concomitant rectal therapy. Thus, aunit dose pharmaceutical product as described herein may include fromabout 0.4 g to about 6 g mesalazine per unit dose, including about 0.4g, about 0.5 g, about 1 g, about 1.2 g, about 2 g, about 2.4 g, about 3g, about 3.6 g, about 4 g, about 4.8 g, about 5 g, or about 6 g, such as0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, or 6 g, and amounts between any of thesevalues.

Compositions

As noted above, in accordance with some embodiments, there are providedcompositions comprising (a) a plurality of delayed-immediate releaseminitablets comprising nicotinamide that selectively releasenicotinamide in the distal ileum and (b) a plurality of delayed-extendedrelease minitablets comprising nicotinamide that selectively releasenicotinamide in the colon. Also provided are compositions comprising (a)a plurality of delayed-immediate release minitablets comprisingnicotinamide that selectively release nicotinamide in the distal ileum,(b) a plurality of delayed-extended release minitablets comprisingnicotinamide that selectively release nicotinamide in the colon, (c) aplurality of delayed-immediate release minitablets comprising mesalazinethat selectively release mesalazine in the distal ileum, and (d) aplurality of delayed-extended release minitablets comprising mesalazinethat selectively release mesalazine in the colon. The minitabletsdescribed herein are compressed tablets provided with one or morecoatings to achieve the desired drug delivery profile.

Minitablets: The Minitablets Matrix

The compressed minitablets of the compositions described herein can haveany shape, such as being spherical, substantially spherical, round,substantially round, oval, oblong, polygonal, etc. The compressedminitablets may have a longest diameter in any dimension of from about 1mm to about 4 mm, including about 2 mm, such as having a longestdiameter of 1 mm, 2 mm, 3 mm, or 4 mm. In some embodiments, thecompressed minitablets have a longest diameter of about 1 mm, about 2mm, about 3 mm, or about 4 mm, including a longest diameter of 1 mm, 2mm, 3 mm, or 4 mm in any dimension.

In some embodiments, the minitablets are comprised of a compressedmatrix (generally excluding any coating) comprising nicotinamide ormesalazine and one or more pharmaceutically acceptable excipients, suchas fillers, binders, lubricants, and the like, as discussed in moredetail below.

In some embodiments, the matrix comprises micronized mesalazine. In someembodiments, the micronized mesalazine has a particle size distributionsuch that the 90th percentile is no more than 30 μm (e.g., D(v,0.9) is30 μm). In some embodiments, the micronized mesalazine has a particlesize distribution such that a typical value of D(v,0.9) is about 16-17μm.

In other embodiments, the matrix comprises mesalazine having D(v,0.9) ofno more than 100 μm, such as mesalazine having a typical value ofD(v,0.9) of about 40-50 μm.

The uncoated nicotinamide matrix of the minitablets may comprise atleast 50% w/w nicotinamide or more, such as at least 60% w/w, at least70% w/w, at least 75% w/w, at least 80% w/w, at least 85% w/w, or atleast 90% w/w nicotinamide, such as about 75-95% w/w, about 80-95% w/w,or about 85-95% w/w. In some embodiments, the uncoated nicotinamideminitablets comprise about 80-90% w/w nicotinamide, including about 80%w/w, 85% w/w, 86% w/w, 87% w/w, 88% w/w, 89% w or 90% w/w nicotinamide.In some embodiments, the uncoated nicotinamide matrix of the minitabletsmay comprise at least 85% w/w nicotinamide or more, such as at least 85%w/w, at least 86% w/w, at least 87% w/w, at least 88% w/w, at least 89%w/w, at least 90% w/w, at least 91% w/w, at least 92% w/w, at least 93%w/w, at least 94% w/w, at least 95% w/w, at least 96% w/w at least 97%w/w at least 98% w/w or at least 99% w/w nicotinamide, such as about85-98% w/w, about 86-98% w/w, about 87-98% w/w, about 88-98% w/w, about89-98% w/w, or about 90-98% w/w. In some embodiments, the uncoatednicotinamide minitablets comprise about 88-98% w/w nicotinamide,including about 88% w/w, 89% w/w, or 90% w/w nicotinamide.

The uncoated mesalazine matrix of the minitablets may comprise at least85% w/w mesalazine or more, such as at least 85% w/w, at least 86% w/w,at least 87% w/w, at least 88% w/w, at least 89% w/w, at least 90% w/w,at least 91% w/w, at least 92% w/w, at least 93% w/w, at least 94% w/w,at least 95% w/w, at least 96% w/w at least 97% w/w at least 98% w/w orat least 99% w/w mesalazine, such as about 85-98% w/w, about 86-98% w/w,about 87-98% w/w, about 88-98% w/w, about 89-98% w/w, or about 90-98%w/w. In some embodiments, the uncoated mesalazine minitablets compriseabout 88-98% w/w mesalazine, including about 88% w/w, 89% w/w, or 90%w/w mesalazine.

The matrix of the minitablets may comprise amounts of the one or morepharmaceutically acceptable excipients sufficient to achieve theintended effect of the excipient(s). A suitable amount of a givenpharmaceutically acceptable excipient can be determined by a person ofordinary skill in the art.

As noted above, the matrix of the minitablets may comprise one or morepharmaceutically acceptable excipients, such as fillers, binders,lubricants, and the like.

Non-limiting examples of fillers include one or more of sucrose,glucose, lactose, mannitol, xylitol, dextrose, microcrystallinecellulose, co-processed microcrystalline celluloses (such as Avicel®CL-611, Avicel® RC-581, Avicel® RC-591, Avicel® CE, Avicel® DG, Avicel®HFE, Avicel® PH-102, Avicel® HFE-102, Avicel® PH-200, and Avicel®PH-302), sugars (such as sucrose, glucose, amylose, maltodextrin,dextrose and the like), maltose, sorbitol, calcium phosphate, calciumsulphate, magnesium aluminium silicate and the like. In someembodiments, the pharmaceutically acceptable filler comprisesmicrocrystalline cellulose.

Non-limiting examples of suitable binders include one or morecelluloses, such as modified celluloses (such as low substitutedhydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC, Hypromellose), hydroxyethylcellulose,hydroxyethyl methylcellulose, and ethyl cellulose), cellulose gum,xanthan gum, carrageenan, chitosan, pectinic acid, sodium alginate,starches such as corn or potato starch partially pregelatinized starches(such as Starch 1500®), polyvinyl acetate (Kollicoat® SR), polyvinylalcohol-polyethylene glycol graft copolymer (Kollicoat® IR),vinylpyrrolidone-vinyl acetate copolymer (copovidone), acrylic acidpolymers (Carbopol®), poloxamers, polycarbophil, polyethylene oxide,polyethylene glycol, polyvinylpyrrolidone (povidone, PVP), and the like.In some embodiments, the pharmaceutically acceptable binder compriseshydroxypropyl cellulose or povidone. In some embodiments, nicotinamideis formulated with hydroxypropyl cellulose as the pharmaceuticallyacceptable binder. In some embodiments, mesalazine is formulated withpovidone as the pharmaceutically acceptable binder.

Non-limiting examples of lubricants include one or more of calciumstearate, glyceryl monostearate, glyceryl palmitostearate, magnesiumstearate, sodium stearyl fumarate, talc powder, and colloidal silicondioxide. In some embodiments, the pharmaceutically acceptable lubricantcomprises magnesium stearate.

Non-limiting examples of disintegrants include one or more of starchessuch as corn or potato starch, modified starches (such as sodium starchglycolate) and partially pregelatinized starches (such as Starch 1500);crosslinked polyvinylpyrrolidone (crospovidone), crosslinkedcarboxymethylcellulose sodium (croscarmellose sodium), ion exchangeresins (such as Polacrilin potassium, Polacrilex) Neusilins, and lowsubstituted hydroxypropyl cellulose.

In some embodiments, the matrix of the delayed-immediate releaseminitablets is the same as the matrix of the delayed-extended releaseminitablets, e.g., the uncoated minitablets are the same. In otherembodiments, the matrix of the delayed-immediate release minitablets isdifferent from the matrix of the delayed-extended release minitablets,e.g., the uncoated minitablets are different.

In some embodiments, the matrix of the delayed-immediate releaseminitablets comprises an active agent (nicotinamide or mesalazine) andone or more of a pharmaceutically acceptable binder, a pharmaceuticallyacceptable filler, and a pharmaceutically acceptable lubricant. In someembodiments, the matrix of the delayed-immediate release minitabletscomprises active agent (nicotinamide or mesalazine) and binder(hydroxypropyl cellulose or povidone). In some embodiments, the matrixof the delayed-immediate release minitablets comprises active agent(nicotinamide or mesalazine), hydroxypropyl cellulose or povidone,microcrystalline cellulose, and magnesium stearate. In some embodiments,the matrix of the delayed-immediate release minitablets comprisesnicotinamide as the active agent and hydroxypropyl cellulose as thebinder. In some embodiments, the matrix of the delayed-immediate releaseminitablets comprises nicotinamide as the active agent, hydroxypropylcellulose as the binder, as well as microcrystalline cellulose andmagnesium stearate. In some embodiments, the matrix of thedelayed-immediate release minitablets comprises mesalazine as the activeagent and povidone as the binder. In some embodiments, the matrix of thedelayed-immediate release minitablets comprises mesalazine as the activeagent, mesalazine as the binder, as well as microcrystalline celluloseand magnesium stearate.

In some embodiments, the matrix of the delayed-extended releaseminitablets comprises an active agent (nicotinamide or mesalazine) andone or more of a pharmaceutically acceptable binder, a pharmaceuticallyacceptable filler, and a pharmaceutically acceptable lubricant. In someembodiments, the matrix of the delayed-extended release minitabletscomprises active agent (nicotinamide or mesalazine) and binder(hydroxypropyl cellulose or povidone). In some embodiments, the matrixof the delayed-extended release minitablets comprises active agent(nicotinamide or mesalazine), binder (hydroxypropyl cellulose orpovidone), microcrystalline cellulose, and magnesium stearate. In someembodiments, the matrix of the delayed-extended release minitabletscomprises nicotinamide as the active agent and hydroxypropyl celluloseas the binder. In some embodiments, the matrix of the delayed-extendedrelease minitablets comprises nicotinamide as the active agent,hydroxypropyl cellulose as the binder, as well as microcrystallinecellulose and magnesium stearate. In some embodiments, the matrix of thedelayed-extended release minitablets comprises mesalazine as the activeagent and povidone as the binder. In some embodiments, the matrix of thedelayed-extended release minitablets comprises mesalazine as the activeagent, mesalazine as the binder, as well as microcrystalline celluloseand magnesium stearate.

Minitablets: The Minitablets Coatings

As noted above, in accordance with some embodiments, the compositionsdescribed herein may comprise a plurality of delayed-immediate releaseminitablets comprising nicotinamide or mesalazine that selectivelyrelease nicotinamide or mesalazine in the distal ileum. In someembodiments, delayed-immediate release is achieved by providingminitablets as described herein with a delayed release coating thatdelays release of nicotinamide or mesalazine from the minitabletssubstantially until the minitablets reach the distal ileum, to achieveselective release in the distal ileum. In some embodiments, the delayedrelease coating is a pH-dependent enteric coating that achieves releaseof nicotinamide or mesalazine at a pH of greater than or equal to about5.5.

As also noted above, in accordance with some embodiments, thecompositions described herein may comprise a plurality ofdelayed-extended release minitablets comprising nicotinamide ormesalazine that selectively release nicotinamide or mesalazine in thecolon. In some embodiments, delayed-extended release is achieved byproviding minitablets as described herein with an inner extended releasecoating and an outer delayed release coating that delays release ofnicotinamide or mesalazine from the minitablets substantially until theminitablets reach the colon, to achieve selective release in the colon.In some embodiments, the inner extended release coating is apH-independent extended release coating and the outer delayed releasecoating is a pH-dependent enteric coating that achieves release ofnicotinamide at a pH of greater than or equal to about 7.

pH-Dependent Enteric Coatings

As noted above, in some embodiments the compositions compriseminitablets provided with a delayed release coating. In someembodiments, the delayed release coating is a pH-dependent entericcoating. In some embodiments, the delayed-immediate release minitabletsare provided with a pH-dependent enteric coating that achievesnicotinamide or mesalazine release at a pH of about 5.5 or greater. Insome embodiments, the delayed-extended release minitablets are providedwith a pH-dependent enteric coating that achieves nicotinamide ormesalazine release at a pH of about 7 or greater.

pH-dependent enteric coatings that achieve release at specific pH valuesare known in the art, and typically comprise polymers with a solubilityin the aqueous environment of the gastrointestinal tract that ispH-dependent (referred to as “enteric polymers”). Typical polymers usedfor this purpose include methacrylic acid copolymers, polysorbatepolymers, cellulose acetate phthalate, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, polyvinylacetate phthalate, cellulose acetate trimellitate,carboxymethylethylcellulose, and shellac. Commercially available entericpolymers include those sold by Evonik Industries under the Eudragit®trademark, including Eudragit® L (methacrylic acid and methylmethacrylate copolymer 1:1), and Eudragit® S (methacrylic acid andmethyl methacrylate copolymer 1:2). For example, Eudragit® L 30 D-55(methacrylic acid and ethyl acrylate copolymer 1:1 dispersion) andEudragit® L-100-55 (methacrylic acid and ethyl acrylate copolymer 1:1)are reported to dissolve above pH 5.5, Eudragit® L 100 (methacrylic acidand methyl methacrylate copolymer 1:1) and Eudragit® L 12.5 (methacrylicacid and methyl methacrylate copolymer 1:1 solution) are reported todissolve above pH 6.0, and Eudragit® S 100 (methacrylic acid and methylmethacrylate copolymer 1:2), Eudragit® S 12.5 (methacrylic acid andmethyl methacrylate copolymer 1:2 dispersion) and Eudragit® FS 30D(poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1dispersion) are reported to dissolve above pH 7.0. Another commerciallyavailable enteric polymer is sold by ShinEtsu as AQOAT® (hypromelloseacetate succinate).

pH-dependent enteric coatings may include a single enteric polymer or amixture of enteric polymers. The relative amounts of the entericpolymers in the delayed release coating and the thickness at which thecoating is applied to the minitablets can be independently selected toachieve release at the intended pH, e.g., at the intended site of thegastrointestinal tract. For example, the polymer(s) can be selected andcombined in relative amounts and applied at a thickness to achievedissolution at the target pH, e.g., at a pH of about 5.5 or a pH ofabout 7 or greater.

In some embodiments, the pH-dependent enteric coating of thedelayed-immediate release minitablets comprises one or more ofmethacrylic acid and ethyl acrylate copolymer (1:1) (e.g., Eudragit® L30D-55), hypromellose acetate succinate, and hypromellose phthalate. Insome embodiments, the pH-dependent enteric coating of thedelayed-extended release minitablets comprises one or more ofmethacrylic acid and methyl methacrylate copolymer 1:2, poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) [7:3:1] (e.g.,Eudragit® FS 30D), and hypromellose acetate succinate. In someembodiments, the pH-dependent enteric coating of the delayed-extendedrelease minitablets comprises methacrylic acid and methyl methacrylatecopolymer 1:2 (e.g., Eudragit® S 100) and triethyl citrate.

pH-Independent Extended Release Coatings

As noted above, in some embodiments the compositions compriseminitablets provided with an extended release coating. In someembodiments, the extended release coating is a pH-independent extendedrelease coating.

pH-independent extended release coatings are known in the art, and maycomprise an extended release polymer and a pore-forming agent.

Extended release polymers suitable for this purpose are known in the artand include hydrophobic polymers with solubility profiles that aresubstantially constant over a pH range of 1-9. Typically, the extendedrelease polymers include pore-forming agents. Pore-forming agentssuitable for this purpose are known in the art, and include agents thatdissolve in an aqueous environment, leaving pores in the coating,thereby allowing release of the active agent through the pores.

Typical extended release polymers used for this purpose includehydrophobic polymers such as cellulose ethers. Non-limiting examples ofsuitable cellulose ethers include ethyl cellulose, cellulose acetate andthe like; polyvinyl esters such as polyvinyl acetate, polyacrylic acidesters, methacrylic and acrylate polymers (pH-independent types); highmolecular weight polyvinyl alcohols and waxes such as fatty acids andglycerides, methacrylic acid ester neutral polymers, polyvinylalcohol-maleic anhydride copolymers and the like;ethylacrylate-methylmethacrylate copolymers; aminoalkyl methacrylatecopolymers; and mixtures thereof. In some embodiments the pH-independentextended release coating includes ethyl cellulose.

Typical pore-forming agents used for this purpose include copovidone;water soluble polymers such as polyvinylpyrrolidone (PVP); water-solublecellulose derived materials, such as hydroxyethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose; inorganic salts;sugars; hydroxylated compounds, including polyvinyl alcohols andglycols, such as polyethylene glycol and propylene glycol; pH-dependentpore formers, such as methacrylic acid copolymers such as Eudragit® L(methacrylic acid and methyl methacrylate copolymer 1:1), Eudragit® S(methacrylic acid and methyl methacrylate copolymer 1:2), Eudragit® FS30D (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)7:3:1), Eudragit® L30D-55 (methacrylic acid and ethyl acrylate copolymer1:1 dispersion) and Eudragit® L100-55 (methacrylic acid and ethylacrylate copolymer 1:1); alginic acid and alginate salts and the like;disintegrants and mixtures of any two or more thereof. In someembodiments the pH-independent extended release coating includeshydroxypropyl methylcellulose (hypromellose) as a pore-forming agent.

Non-limiting examples of disintegrants include one or more of starchessuch as corn or potato starch, modified starches (such as sodium starchglycolate) and partially pregelatinized starches (such as Starch 1500);crosslinked polyvinylpyrrolidone (crospovidone), crosslinkedcarboxymethylcellulose sodium (croscarmellose sodium), ion exchangeresins (such as Polacrilin potassium, Polacrilex) Neusilins, and lowsubstituted hydroxypropyl cellulose. In some embodiments disintegrantscan be used as pore-forming agents.

Alternatively, a pH-independent extended release coatings may comprise awaxy material and a hydrophilic polymer. Typical waxy materials used forthis purpose include hydrophobic waxy materials, such as one or more ofcarnauba wax, white wax, candelilla wax, beeswax, cetylester wax, montanwax, microcrystalline wax, lecithin, hydrogenated tallow, paraffin wax,sellac wax, paraffin soft, glyceryl behenate, glycerylpalmitoesterarate, glyceryl diestearate, tribehenin, glycerol esterssuch as glyceryl behenate and glyceryl palmitostearate, fatty alcohols(particularly those having 12-24 carbon atoms, such as cetyl alcohol,cetostearyl alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol,palmityl alcohol, etc.), fatty acids (particularly those having 12-24carbon atoms, such as lauric acid, myristic acid, stearic acid, palmiticacid, etc.), castor wax (i.e., hydrogenated castor-oil), C₁₆₋₃₀ fattyacid triglycerides, stearyl polyoxil-32 glyceride, behenoyl polyoxil-8glyceride, lauroyl polyoxil glycerides, and steral polyoxil glycerides.For example, the waxy material may comprise one or more of white wax,glyceryl behenate, glyceryl palmitoesterarate and fatty alcohols such ascetyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol,stearyl alcohol and palmityl alcohol.

Typical hydrophilic polymers used for this purpose include one or moreof polyvinyl alcohol, sodium carboxy methylcellulose,hydroxypropylcellulose, hydroxypropylmethyl cellulose,hydroxyethylmethylcellulose, polyvinylpyrrolidone, copovidone starch orits derivatives, sodium alginate, calcium alginate, sodiumcarboxymethylcellulose, calcium carboxymethylcellulose, polyethyleneglycol (PEG) having a molecular weight of greater than 1000 numberaverage molecular weight (e.g., PEG 3350, PEG 4600, PEG 6000, PEG 8000,PEG 12000 and PEG 20000), polyethylene oxide, and enteric polymers.

In some embodiments, the extended release coating comprises ethylcellulose and a pore-forming agent, such as hydroxypropylmethylcellulose.

The relative amounts of extended release polymer and pore-forming agent(or waxy substance and hydrophilic polymer) in the extended releasecoating and the thickness at which the coating is applied to theminitablets can be independently selected to achieve the desiredextended release profile. For example, increasing the relative amount ofpore-forming agent generally will increase the release rate, andincreasing the thickness of the coating on the minitablets generallywill decrease the release rate. Exemplary extended release coatingweights are illustrated in the examples, and include coating weights offrom about 2% to about 25%. In some embodiments, an extended releasecoating is applied to a nicotinamide minitablet at a coating weight offrom about 9% to about 25%. In some embodiments, an extended releasecoating is applied to a mesalazine minitablet at a coating weight offrom about 3% to about 10%.

Any coating as described herein also may include a lubricant and/or aplasticizer. Typical lubricants used for this purpose include one ormore of calcium stearate, glyceryl monostearate, glycerylpalmitostearate, magnesium stearate, sodium stearyl fumarate and sodiumlauryl sulfate. In some embodiments, a coating includes a lubricant.Typical plasticizers used for this purpose include one or more ofglycerin, polyethylene glycols, polyethylene glycol monomethyl ether,propylene glycol, sorbitol sorbitan solution, acetyl tributyl citrate,acetyl triethyl citrate, castor oil, diacetylated monoglycerides,dibutyl sebacate, diethyl phthalate, triacetin, tributyl citrate,triethyl citrate, glyceryl monostearate, glyceryl palmitostearate, andsodium stearyl fumarate. In some embodiments, a coating includes aplasticizer, such as dibutyl sebacate or triethyl citrate.

Any coating as described herein also may include other components, suchas an anti-tack agent such as talc, and/or colloidal silicon dioxide,calcium stearate, magnesium stearate, and combinations of any two ormore thereof. In some embodiments, a coating includes talc.

Any coating as described herein also may include a surfactant. Typicalsurfactants used for this purpose include one or more of sodiumdodecylsulfate, polysorbate 80, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, polysorbate 85, polysorbate 80,polysorbate 21, polysorbate 61, poloxamer 188, and macrogolglycerolricinoleate.

Delayed-Immediate Release Tablets

As noted above, the nicotinamide delayed-immediate release minitablets(DR/IR minitablets) described herein comprise a compressed matrixcomprising nicotinamide as described above provided with a pH-dependententeric coating as described above. In some embodiments, thenicotinamide delayed-immediate release minitablets selectively releasenicotinamide in the distal ileum. In some embodiments, thedelayed-immediate release minitablets release nicotinamide at a pH ofabout 5.5 or greater. In some embodiments, the delayed-immediate releaseminitablets selectively release nicotinamide in the distal ileum, andmay continue to release nicotinamide lower/later in the digestive tract.In some embodiments, the delayed-immediate release minitablets do notrelease more than 25% w/w, more than 30% w/w, more than about 40% w/w,or more than about 50% w/w of the total amount of nicotinamide until theminitablets reach the distal ileum, and/or release at least about 50%w/w of their total nicotinamide content in the distal ileum, such as atleast 50% w/w, about 50% w/w, at least 60% w/w, about 60% w/w, at least70% w/w, about 70% w/w, at least 75% w/w, about 75% w/w, or greater, inthe distal ileum.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7 buffer, the nicotinamidedelayed-immediate release minitablets exhibit release of less than 10%of their total nicotinamide content at pH 1.2 and pH 4.5 (e.g. at 4hours), and exhibit release of substantially all of their totalnicotinamide content within 60 minutes at pH 7.

The delayed-immediate release of nicotinamide at a pH of about 5.5 orabove achieved by the nicotinamide DR/IR minitablets achieves targeteddelivery and selective release of nicotinamide to the distal ileum, thusproviding nicotinamide to the distal ileum where it can exerttherapeutic effect.

As noted above, the mesalazine delayed-immediate release minitablets(DR/IR minitablets) described herein comprise a compressed matrixcomprising mesalazine as described above provided with a pH-dependententeric coating as described above. In some embodiments, thedelayed-immediate release minitablets selectively release mesalazine inthe distal ileum. In some embodiments, the mesalazine delayed-immediaterelease minitablets release mesalazine at a pH of about 5.5 or greater.In some embodiments, the delayed-immediate release minitabletsselectively release mesalazine in the distal ileum, and may continue torelease mesalazine lower/later in the digestive tract. In someembodiments, the delayed-immediate release minitablets release at leastabout 50% w/w of their total mesalazine content in the distal ileum,such as at least 50% w/w, about 50% w/w, at least 60% w/w, about 60%w/w, at least 70% w/w, about 70% w/w, or greater, in the distal ileum.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7 buffer, mesalazinedelayed-immediate release minitablets described herein exhibitsubstantially no release of mesalazine at pH 1.2 and pH 4.5, and releasesubstantially all mesalazine within 120 minutes at pH 7.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7 buffer, mesalazinedelayed-immediate release minitablets described herein exhibitsubstantially no release of mesalazine at pH 1.2 and pH 4.5, and releasesubstantially all mesalazine within 90 minutes at pH 7.

The delayed-immediate release of mesalazine at a pH of about 5.5 orabove achieved by the mesalazine DR/IR minitablets achieves targeteddelivery and selective release of mesalazine to the distal ileum, thusproviding mesalazine to the distal ileum where it can exert therapeuticeffect.

Delayed-Extended Release Tablets

As noted above, the nicotinamide delayed-extended release minitablets(DR/ER minitablets) described herein comprise a compressed matrixcomprising nicotinamide as described above provided with an innerpH-independent extended release coating as described above and an outerpH-dependent enteric coating as described above. In some embodiments,the nicotinamide delayed-extended release minitablets selectivelyrelease nicotinamide in the colon. In some embodiments, the nicotinamidedelayed-extended release minitablets described herein releasenicotinamide at a pH of about 7 or above. In some embodiments, thedelayed-extended release minitablets do not release more than 25%, w/wmore than 30% w/w, more than about 40% w/w, or more than about 50% w/wof the total amount of nicotinamide until the minitablets reach thecolon, and/or release at least about 50% w/w of their total nicotinamidecontent in the colon, such as at least 50% w/w, about 50% w/w, at least60% w/w, about 60% w/w, at least 70% w/w, about 70% w/w, at least 75%w/w, about 75% w/w or greater, in the colon.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, thenicotinamide delayed-extended release minitablets exhibit substantiallyno release of nicotinamide at pH 1.2 and pH 4.5, and exhibit extendedrelease of nicotinamide over at least 4 hours at pH 7.0.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, thenicotinamide delayed-extended release minitablets exhibit substantiallyno release of nicotinamide at pH 1.2 and pH 4.5, and exhibit extendedrelease of nicotinamide over at least 6 hours, over at least 8 hours, orover at least 12 hours at pH 7.0. In some embodiments, delayed-extendedrelease tablets may exhibit at least 90% release of nicotinamide within12 hours, within 18 hours, within 24 hours, within 36 hours, or within48 hours at pH 7.0 or greater.

The delayed-extended release of nicotinamide achieved by thenicotinamide DR/ER minitablets achieves targeted delivery and selective,extended release of nicotinamide in the colon, thus providingnicotinamide to the colon where it can exert therapeutic effect.

As noted above, the mesalazine delayed-extended release minitablets(DR/ER minitablets) described herein comprise a compressed matrixcomprising mesalazine as described above provided with an innerpH-independent extended release coating as described above and an outerpH-dependent enteric coating as described above. In some embodiments,the mesalazine delayed-extended release minitablets selectively releasemesalazine in the colon. In some embodiments, the mesalazinedelayed-extended release minitablets described herein release mesalazineat a pH of about 7 or above.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, mesalazinedelayed-extended release minitablets described herein exhibitsubstantially no release of mesalazine at pH 1.2 and pH 4.5, and exhibitextended release of mesalazine over at least 4 hours at pH 7.0. In someembodiments, delayed-extended release tablets may exhibit at least 90%release of mesalazine within 12 hours, within 18 hours, within 24 hours,within 36 hours, or within 48 hours at pH 7.0 or greater.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Type 1 Basket at 37° C. and 100 rpm in 500 mLdissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5buffer for 2 hours, followed by pH 7.0 buffer for 12 hours, mesalazinedelayed-extended release minitablets exhibit substantially no release ofmesalazine at pH 1.2 and pH 4.5, and exhibit extended release ofmesalazine over 12 hours at pH 7.0. In some embodiments,delayed-extended release tablets may exhibit at least 90% release ofmesalazine within 12 hours, within 18 hours, within 24 hours, within 36hours, or within 48 hours at pH 7.0 or greater.

The delayed-extended release of mesalazine achieved by the mesalazineDR/ER minitablets achieves targeted delivery and selective, extendedrelease of mesalazine in the colon, thus providing mesalazine to thecolon where it can exert therapeutic effect.

Other Coatings

Any of the minitablets described herein may further comprise anadditional pharmaceutically acceptable coating. For example, any, someor all of minitablets described herein may be provided with a seal coatexterior to the pH-dependent enteric coating and/or a colored coatingexterior to the pH-dependent enteric coating.

Unit Dose Pharmaceutical Products

As noted above, also provided herein are unit dose pharmaceuticalproducts comprising (a) a plurality of delayed-immediate releaseminitablets as described herein that selectively release nicotinamide inthe distal ileum and (b) a plurality of delayed-extended releaseminitablets as described herein that selectively release nicotinamide inthe colon. As noted above, also provided herein are unit dosepharmaceutical products comprising (a) a plurality of delayed-immediaterelease minitablets comprising nicotinamide that selectively releasenicotinamide in the distal ileum, (b) a plurality of delayed-extendedrelease minitablets comprising nicotinamide that selectively releasenicotinamide in the colon, (c) a plurality of delayed-immediate releaseminitablets comprising mesalazine that selectively release mesalazine inthe distal ileum, and (d) a plurality of delayed-extended releaseminitablets comprising mesalazine that selectively release mesalazine inthe colon.

A unit dose pharmaceutical product as described herein may comprise aunit dose of nicotinamide, which may be a therapeutically effectiveamount of nicotinamide, including a therapeutically effective daily doseof nicotinamide or a divided dose of a therapeutically effective dailydose of nicotinamide. As discussed above, a therapeutically effectiveamount of nicotinamide for influencing the gastrointestinal microbiotaor treating gastroinstestinal inflammation, including inflammatory boweldisease is generally about 2 to 3 g/day for an adult human subject,optionally administered in two to four divided doses (e.g., 1 g twotimes a day, 0.5 g four times a day, etc.). Thus, a unit dosepharmaceutical product as described herein may include from about 0.25 gto about 6 g nicotinamide per unit dose, including about 0.25 g, about0.5 g, about 0.75 g, about 1 g, about 1.25 g, about 1.5 g, about 1.75 g,about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g,about 5 g, about 5.5 g, or about 6 g, such as 0.25 g, 0.5 g, 0.75 g, 1g, 1.25 g, 1.5 g, 1.75 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5g, or 6 g, and amounts between any of these values. In some embodiments,the amount of nicotinamide is effective to modulate gastrointestinalmicrobiota and thereby exert a therapeutic effect in inflammatory bowelconditions where microbiota play a pathogenic role, such as ulcerativecolitis and Crohn's disease.

A unit dose pharmaceutical product as described herein may be formulatedto deliver one amount of nicotinamide to the distal ileum and to delivera second amount of nicotinamide to the colon, by providing a firstselected amount of nicotinamide in the delayed-immediate release (DR/IR)minitablets and a second selected amount of nicotinamide in thedelayed-extended release (DR/ER) minitablets. The amounts ofnicotinamide provided in each type of minitablets may be selected basedon the specific disease or condition being treated, such as the natureand extent of the disease state in various regions of the digestivetract, such as the distal ileum and/or colon. Thus, from about 10 toabout 90% w/w of the nicotinamide provided in a unit dose pharmaceuticalproduct may be present in the delayed-immediate release (DR/IR)minitablets, and from about 90 to about 10% w/w of the nicotinamide maybe present in the delayed-extended release (DRIER) minitablets. Forexample about 10% w/w, 20% w/w, 25% w/w, 30% w/w, 33% w/w, 40% w/w, 50%w/w, 60% w/w, 66% w/w, 70% w/w, 75% w/w, 80% w/w, or 90% w/w (or anyamount between these values) of the nicotinamide provided in a unit dosepharmaceutical product may be present in the delayed-extended release(DRIER) minitablets, based on the total weight of the nicotinamideprovided in the delayed-immediate release minitablets and thedelayed-extended release minitablets. Thus, 10% w/w, 20% w/w, 25% w/w,30% w/w, 33% w/w, 40% w/w, 50% w/w, 60% w/w, 66% w/w, 70% w/w, 75% w/w,80% w/w, or 90% w/w of the nicotinamide, or any amount between thesevalues, is provided in the DR/IR minitablets. In some embodiments, about50% w/w of the nicotinamide provided in a unit dose pharmaceuticalproduct is present in the delayed-immediate release minitablets. In someembodiments, less than 50% w/w of the nicotinamide provided in a unitdose pharmaceutical product is present in the delayed-immediate releaseminitablets, In some embodiments, greater than 50% w/w of thenicotinamide provided in a unit dose pharmaceutical product is presentin the delayed-immediate release minitablets.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Apparatus 2 at 37° C. and 100 rpm in 750 mL of 0.1N HCLfor 2 hours, followed by 1000 mL of pH 7 phosphate buffer for 12 hours,a unit dose pharmaceutical product having 50% w/w of the nicotinamideprovided in the DR/IR minitablets and 50 w/w of the nicotinamideprovided in the DR/ER minitablets exhibits release of nicotinamide of≤10% at 2 hours, 60-90% at 6 hours, and ≥90% at 14 hours.

In some embodiments, a unit dose pharmaceutical product is in the formof a sachet, capsule or vial containing a unit dose of DR/IR and DR/ERnicotinamide minitablets.

As noted above, a unit dose pharmaceutical product as described hereinalso may comprise a unit dose of mesalazine, which may be atherapeutically effective amount of mesalazine, including atherapeutically effective daily dose of mesalazine or a divided dose ofa therapeutically effective daily dose of mesalazine. As discussedabove, a therapeutically effective amount of mesalazine for thetreatment of gastrointestinal inflammation, including inflammatory boweldisease is generally about 2 to about 6 g per day for an adult humansubject, optionally administered in two to four divided doses (e.g.,about 4 g once a day, about 2 g two times a day, about 1 g four times aday, etc.). For example, therapeutic doses of mesalamine for patientswith active ulcerative colitis of any disease extent beyond proctitis istypically from about 2 to about 5 g a day, including from about 2.4 toabout 4.8 g/day, with or without concomitant rectal therapy. Thus, aunit dose pharmaceutical product as described herein may include fromabout 0.4 g to about 6 g mesalazine per unit dose, including about 0.4g, 0.5 g, about 1 g, about 1.2 g, about 2 g, about 2.4 g, about 3 g,about 3.6 g, about 4 g, about 4.8 g, about 5 g, or about 6 g, such as0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, or 6 g, and amounts between any of thesevalues.

In some embodiments, the nicotinamide may potentiate the therapeuticeffect of the mesalazine such that a lower amount of mesalazine may be atherapeutically effective amount, different than the amount required inthe absence of nicotinamide. Additionally or alternatively, in someembodiments, the mesalazine may potentiate the therapeutic effect of thenicotinamide such that a lower amount of nicotinamide may be atherapeutically effective amount, different than the amount required inthe absence of mesalazine. In some embodiments, the therapeuticallyeffective amounts of nicotinamide and mesalazine provided in a unit dosepharmaceutical product reflect that the nicotinamide and/or mesalazinepotentiate the therapeutic effect of the other active agent. Thus, insome embodiments, a unit dose pharmaceutical product comprises atherapeutically effective amount of mesalazine that is lower than theamounts set forth above. Additionally or alternatively, in someembodiments, a unit dose pharmaceutical product comprises atherapeutically effective amount of nicotinamide that is lower than theamounts set forth above.

A unit dose pharmaceutical product as described herein may be formulatedto deliver one amount of mesalazine to the distal ileum and to deliver asecond amount of mesalazine to the colon, by providing a first selectedamount of mesalazine in the delayed-immediate release (DR/IR)minitablets and a second selected amount of mesalazine in thedelayed-extended release (DR/ER) minitablets. The amounts of mesalazineprovided in each type of minitablet may be selected based on thespecific disease or condition being treated, such as the nature andextent of the disease state in various regions of the digestive tract,such as the distal ileum and/or colon.

Thus, from about 10 to about 90% w/w of the mesalazine provided in aunit dose pharmaceutical product may be present in the delayed-immediaterelease (DR/IR) minitablets, and from about 90 to about 10% w/w of themesalazine may be present in the delayed-extended release (DR/ER)minitablets. For example at least 50% w/w, such as about 50% w/w, or atleast 70% w/w, such as about 70% w/w, about 75% w/w, about 80% w/w, orgreater, of the mesalazine provided in a unit dose pharmaceuticalproduct may be present in the delayed-extended release (DR/ER)minitablets, based on the total weight of the mesalazine provided in thedelayed-immediate release minitablets and the delayed-extended releaseminitablets. In some embodiments, about 50% w/w of the mesalazineprovided in the unit dose pharmaceutical product is provided in theDR/IR minitablets and about 50% w/w of the mesalazine is provided in theDR/ER minitablets. In other embodiments, at least about 50% w/w, atleast about 60% w/w, at least about 70% w/w, at least about 75% w/w, orat least about 80% w/w of the mesalazine is provided in the DR/ERminitablets, such as 50% w/w, from 50-80% w/w, about 60% w/w, about 65%w/w, about 70% w/w, about 70% w/w, about 75% w/w, about 75% w/w, about80% w/w, about 85% w/w, and about 90% w/w of the mesalazine beingprovided in the DR/ER minitablets.

In some embodiments, when subject to in vitro dissolution testingaccording to USP Apparatus 2 at 37° C. and 100 rpm in 750 mL of 0.1N HCLfor 2 hours, followed by 1000 mL of pH 7 phosphate buffer for 12 hours,a unit dose pharmaceutical product as described herein exhibits releaseof mesalazine of ≤10% at 2 hours, 45-75% at 6 hours, and ≥90% at 14hours.

The relative amount of nicotinamide provided in the delayed-immediaterelease (DR/IR) minitablets versus the delayed-extended release (DR/ER)minitablets can be selected independently of the relative amount ofmesalazine provided in the delayed-immediate release (DR/IR) minitabletsversus the delayed-extended release (DR/ER) minitablets. Thus, a unitdose pharmaceutical product as described herein may be formulated todeliver one amount of nicotinamide to the distal ileum, to deliver asecond amount of nicotinamide to the colon, to deliver one amount ofmesalazine to the distal ileum, and to deliver a second amount ofmesalazine to the colon, where each amount can be independently selectedbased on, for example, the particular subject or condition beingtreated, the purpose for which the product is being used (e.g.,treatment of an active disease state versus remission), etc.

In some embodiments, a unit dose pharmaceutical product is in the formof a sachet, capsule or vial containing a unit dose of DR/IR and DR/ERmesalazine minitablets and a unit dose of DR/IR and DR/ER nicotinamideminitablets.

Methods of Manufacture

The compositions described herein can be made by methods known in art.In general the minitablet matrices can be manufactured by wetgranulation, roller compaction or direct compression processes. In someembodiments, the DR/IR minitablets are made by coating minitabletsmatrices with a pH-dependent enteric coating. In some embodiments, theDR/ER minitablets are made by coating minitablets matrices with apH-independent extended release coating and a pH-dependent entericcoating, with appropriate drying times between coatings. Unit dosepharmaceutical products are prepared by filling a container (e.g., asachet, capsule or vial) with a unit dose of the DR/IR and DR/ERminitablets.

In some embodiments, the minitablet matrices have a hardness of about1.0-3.0 kp, including a hardness of about 1.0, about 2.0, or about 3.0kp. In some embodiments, the minitablet matrices have a friability of nomore than about 1.0%. In some embodiments, the minitablet matrices havea friability of no more than about 0.7%. In some embodiments, theminitablet matrices have a friability of no more than about 0.5%.

In some embodiments illustrated in FIG. 1 , minitablets matrices aremade by a process wherein the nicotinamide, a filler, and a binder aregranulated, dried in an oven, and milled. The milled granules are thenblended with a lubricant and then compressed into minitablet matrices ofthe desired weight, hardness, thickness, and friability.

In some embodiments illustrated in FIG. 2 and FIG. 3 , the mesalazine, afiller, and a binder are granulated, dried in an oven, and milled. Themilled granules are then blended with a lubricant and then compressedinto minitablets of the desired weight, hardness, thickness, andfriability.

To prepare DR/IR minitablets, in some embodiments, compressed minitabletmatrices are coated with a pH-dependent enteric coating and may becured, such as in an oven. A seal coat may be applied to the cured DR/IRtablets.

To prepare DR/ER minitablets, in some embodiments, compressed minitabletmatrices are coated with a pH-independent extended release coating, andmay be cured, such as in an oven. A pH-dependent enteric coating may beapplied as an outer coating to the pH-independent coated minitabletmatrices, which may be cured again, such as in an oven. A seal coat maybe applied to the doubly-coated DR/ER minitablets.

Therapeutic Methods

Also provided herein are methods of administering nicotinamide or acombination of nicotinamide and mesalazine, to a subject in needthereof, comprising orally administering to the subject a composition orunit dose pharmaceutical product as described herein. The subject may bein need of alteration of the gastrointestinal microbiota, or may besuffering from or at risk of developing gastrointestinal inflammation,such as inflammatory bowel disease, including ulcerative colitis orCrohn's disease. The subject may be suffering from active inflammatorybowel disease or may be in remission. Thus, treating a subject includesreducing the symptoms and/or duration of active inflammatory boweldisease and increasing the length of remission periods (e.g., reducingthe likelihood of flares). In some embodiments, the subject is sufferingfrom or in remission from an inflammatory bowel condition wheremicrobiota play a pathogenic role, such as ulcerative colitis andCrohn's disease.

As described above, oral administration of the compositions describedherein provide delayed-immediate release (e.g., “burst” release) ofnicotinamide or nicotinamide and mesalazine in the distal ileum and alsoprovide extended release of nicotinamide or nicotinamide and mesalazinein the colon. While not wanting to be bound by theory, it is believedthat subjects suffering from ulcerative colitis may particularly benefitfrom the methods described herein, since such subjects have moreextensive disease (e.g., more extensive inflammation in the distal ileumand colon). Again, while not wanting to be bound by theory, subjectssuffering from pancolitis or extensive colitis (e.g., occurring beyondthe explenic flexure) and/or with backwash ileitis (e.g., inflammationof terminal ileum in ulcerative colitis) may particularly benefit fromthe methods described herein, e.g., from being treated by oraladministration of compositions providing a “burst” release ofnicotinamide and/or mesalazine in the distal ileum and also extendedrelease of nicotinamide or nicotinamide and mesalazine in the colon,since such patients would benefit from the local action of nicotinamideor nicotinamide and mesalazine at those sites.

While not wanting to be bound by theory, it also is believed thatsubjects suffering from Crohn's disease would benefit from the methodsdescribed herein, particularly those subjects suffering from ileal,ileocolonic or colonic disease.

While not wanting to be bound by theory, it also is believed thatsubjects suffering from an inflammatory bowel condition where microbiotaplay a pathogenic role would benefit from the methods described herein.

Thus, also provided herein are methods of influencing thegastrointestinal microbiota and/or treating gastrointestinalinflammation, such as inflammatory bowel disease, including ulcerativecolitis or Crohn's disease, comprising orally administering to a subjectin need thereof a composition or unit dose pharmaceutical product asdescribed herein, comprising nicotinamide or nicotinamide andmesalazine. As noted above, a suitable subject may be suffering from oneor more of ulcerative colitis, pancolitis, extensive colitis, backwashileitis, and/or one more of Crohn's disease, ileal disease, ileocolonicdisease and colonic disease.

The methods may comprise administering a composition or unit dosepharmaceutical product as described herein one or more times per day,such as one, two, three, four, five, or more, times per day. In someembodiments, a unit dose pharmaceutical product is administered once aday. In some embodiments, a unit dose pharmaceutical product isadministered twice a day. In some embodiments, a unit dosepharmaceutical product is administered three times a day. In someembodiments, a unit dose pharmaceutical product is administered fourtimes a day. In some embodiments, a unit dose pharmaceutical product isadministered five times a day.

EXAMPLES

The following specific examples are included as illustrative of thecompositions and unit dose pharmaceutical products described herein.These examples are in no way intended to limit the scope of thedisclosure. Other aspects of the disclosure will be apparent to thoseskilled in the art to which the disclosure pertains.

The following procedures can be used to produce compositions and unitdose pharmaceutical products described above.

Example 1: Nicotinamide Delayed-Immediate Release Minitablets

The matrices for the minitablets can be made by granulating nicotinamideand a carrier such as microcrystalline cellulose with a binder such ashydroxypropyl cellulose (e.g., a hydroalcoholic solution ofhydroxypropyl cellulose), for example using a fluid bed top-spraygranulation process, and then drying the granules, such as in an oven,for example until loss on drying (LOD) is below 1.0%. The dried granulesthen can be milled and the milled granules can be blended with alubricant such as magnesium stearate, such as by using a V-blender. Theminitablets can then be formed by compressing the matrix blend, such asby using a rotary tablet press. These steps are illustrated in the topthird of FIG. 1 .

DR/IR minitablets can be made by coating the compressed minitablets,such as by using a fluid bed coater apparatus, using a delayed-releasecoating, such as an enteric coating composition comprising an aqueoussuspension of Eudragit® L30D-55 containing a plasticizer such as dibutylsebacate and an anti-tack agent such as talc, followed by curing. Anoptional seal coat can be applied onto the cured DR/IR minitablets, suchas by using a fluid bed coater apparatus. These steps are illustrated inthe left side of the middle third of FIG. 1 .

A dissolution profile for DR/IR minitablets made in this manner is shownin FIG. 4 . For all examples, dissolution was measured by in vitrodissolution testing according to USP Type 1 Basket at 37° C. and 100 rpmin 500 mL dissolution medium of pH 1.2 buffer for 2 hours, followed bypH 4.5 buffer for 2 hours, followed by pH 7 buffer.

Example 2: Nicotinamide Delayed-Immediate Release Minitablets

Nicotinamide minitablets matrices prepared as described in Example 1 canbe used to prepare DR/IR minitablets by coating the compressedminitablets, such as by using a fluid bed coater apparatus, with adelayed-release coating, such as an enteric coating compositioncomprising an aqueous suspension of hypromellose acetate succinate(AQOAT®)) containing a plasticizer such as triethyl citrate, ananti-tack agent such as talc, and a lubricant or surfactant such assodium lauryl sulfate.

A dissolution profile for DR/IR minitablets made in this manner is shownin FIG. 5 .

Example 3: Nicotinamide Delayed-Extended Release Minitablets

Nicotinamide minitablets matrices prepared as described in Example 1 canbe used to prepare DR/ER minitablets by coating the compressedminitablets, such as by using in a fluid bed coater apparatus, with anextended release coating (such as a hydroalcoholic suspension containingethylcellulose, hypromellose, triethyl citrate and talc), applied at acoating weight of approximately 9%.

The ER-coated minitablets are further coated with delayed-releasecoating, such as by using a fluid bed coater apparatus, with an aqueousdispersion of a delayed-release coating (such as a compositioncomprising Eudragit® FS30D and PlasACRYL™ T20), followed by curing. Anoptional seal coat can be applied onto the cured DR/ER minitablets, suchas by using a fluid bed coater apparatus. These steps are illustrated inthe right side of the middle third of FIG. 2 .

A dissolution profile for DR/ER minitablets made in this manner is shownin FIG. 6 .

Example 4: Nicotinamide Delayed-Extended Release Minitablets

Nicotinamide DR/ER minitablets can be made as described above using asthe extended release coating a hydroalcoholic coating suspensioncontaining ethylcellulose, hypromellose, triethyl citrate and talc,applied at a coating weight of approximately 17%, and using as thedelayed-release coating an aqueous dispersion of Eudragit® FS30D andPlasACRYL™ T20.

A dissolution profile for DR/ER minitablets made in this manner is shownin FIG. 7 .

Example 5: Nicotinamide Delayed-Extended Release Mini Tablets

Nicotinamide DR/ER minitablets can be made as described above using asthe extended release coating a hydroalcoholic coating suspensioncontaining ethylcellulose, hypromellose, triethyl citrate and talc,applied at a coating weight of approximately 25%, and using as thedelayed-release coating an aqueous dispersion of Eudragit® FS30D andPlasACRYL™ T20.

A dissolution profile for DR/ER minitablets made in this manner is shownin FIG. 8 .

Example 6: Nicotinamide DR/IR Minitablets+DR/ER Minitablets

Nicotinamide DR/IR minitablets prepared as described in Example 1 andDR/ER minitablets prepared as described in Example 5 are combined in a30:70 ratio. A dissolution profile for the combination product is shownin FIG. 9 .

To prepare a pharmaceutical product, the combined DR/IR and DR/ERminitablets can be filled into a container, as illustrated in the bottomthird of FIG. 1 . To prepare a unit dose pharmaceutical product, a unitdose of the combined DR/IR and DR/ER minitablets can be filled into acontainer.

Example 7: Nicotinamide DR/IR Minitablets+DR/ER Minitablets

Nicotinamide DR/IR minitablets prepared as described in Example 1 andDR/ER minitablets prepared as described in Example 5 are combined in a50:50 ratio. A dissolution profile for the combination product is shownin FIG. 10 .

To prepare a pharmaceutical product, the combined DR/IR and DR/ERminitablets can be filled into a container, as illustrated in the bottomthird of FIG. 1 . To prepare a unit dose pharmaceutical product, a unitdose of the combined DR/IR and DR/ER minitablets can be filled into acontainer.

Example 8: Mesalazine Delayed-Immediate Release Minitablets

The matrices for the mesalazine minitablets can be made by granulatingmesalazine and a carrier such as microcrystalline cellulose with abinder such as povidone (e.g., an aqueous solution of povidone), forexample using a high-shear granulation process, and then drying thegranules, such as in an oven, for example until loss on drying (LOD) isbelow 3.0%. The dried granules then can be milled and the milledgranules can be blended with a lubricant such as magnesium stearate,such as by using a V-blender. The minitablets can then be formed bycompressing the matrix blend, such as by using a rotary tablet press.These steps are illustrated in the top third of FIG. 2 and FIG. 3 .

DR/IR minitablets can be made by coating the compressed minitablets,such as by using a fluid bed coater apparatus, using delayed-releasecoating, such as an enteric coating composition comprising an aqueoussuspension of Eudragit® L30D-55) containing a plasticizer such asdibutyl sebacate and an anti-tack agent such as talc, followed bycuring. An optional seal coat can be applied onto the cured DR/IRminitablets, such as by using a fluid bed coater apparatus. These stepsare illustrated in the left side of the middle third of FIG. 2 and FIG.3 .

A dissolution profile for DR/IR minitablets made in this manner is shownin FIG. 11 .

Example 9: Mesalazine Delayed-Immediate Release Minitablets

Mesalazine minitablets matrices prepared as described in Example 8 canbe used to prepare DR/IR minitablets by coating the compressedminitablets, such as by using a fluid bed coater apparatus, with anextended-release coating (such as an enteric coating compositioncomprising an aqueous suspension of hypromellose acetate succinate(AQOAT®)) containing a plasticizer such as triethyl citrate, ananti-tack agent such as talc, and sodium lauryl sulfate.

A dissolution profile for DR/IR minitablets made in this manner is shownin FIG. 12 .

Example 10: Mesalazine Delayed-Extended Release Minitablets

Mesalazine minitablets matrices prepared as described in Example 8 canbe used to prepare DR/ER minitablets by coating the compressedminitablets, such as by using a fluid bed coater apparatus, with anextended release coating (such as a hydroalcoholic coating suspensioncontaining ethylcellulose, hypromellose, triethyl citrate and talc),applied at a coating weight of approximately 3%. After curing, theER-coated minitablets are further coated with a delayed-release coating,such as by using a fluid bed coater apparatus, with an aqueousdispersion of a delayed-release coating (such as a compositioncomprising Eudragit® FS30D and PlasACRYL™ T20), followed by curing. Anoptional seal coat can be applied onto the cured DR/ER minitablets, suchas by using a fluid bed coater apparatus. These steps are illustrated inthe right side of the middle third of FIG. 2 and FIG. 3 .

A dissolution profile for DR/ER minitablets made in this manner is shownin FIG. 13 .

Example 11: Mesalazine Delayed-Extended Release Minitablets

Mesalazine DR/ER minitablets can be made as described above using as theextended release coating a hydroalcoholic coating suspension containingethylcellulose, hypromellose, triethyl citrate and talc, applied at acoating weight of approximately 7.5%, and using as the delayed-releasecoating an aqueous dispersion of Eudragit® FS30D and PlasACRYL™ T20.

A dissolution profile for DR/ER minitablets made in this manner is shownin FIG. 14 .

Example 12: Mesalazine Delayed-Extended Release Minitablets

Mesalazine DR/ER minitablets can be made as described above using as theextended release coating a hydroalcoholic coating suspension containingethylcellulose, hypromellose, triethyl citrate and talc, applied at acoating weight of approximately 10%, and using as the delayed-releasecoating an aqueous dispersion of Eudragit® FS30D and PlasACRYL™ T20.

A dissolution profile for DR/ER minitablets made in this manner is shownin FIG. 15 .

Example 13: Mesalazine Delayed-Extended Release Minitablets

Mesalazine DRIER minitablets can be made as described above using as theextended release coating a hydroalcoholic coating suspension containingethylcellulose and hypromellose, applied at a coating weight ofapproximately 3%, and using as the delayed-release coating an aqueousdispersion of Eudragit® FS30D and PlasACRYL™ T20.

A release profile for mesalazine DR/ER minitablets made in this manneris shown in FIG. 16 .

Example 14: Mesalazine Delayed-Extended Release Minitablets

Mesalazine DR/ER minitablets can be made as described above using as theextended release coating a hydroalcoholic coating suspension containingethylcellulose and hypromellose, applied at a coating weight ofapproximately 5%, and using as the delayed-release coating an alcoholicsolution of Eudragit S 100 and triethyl citrate.

A release profile for Mesalazine DR/ER minitablets made in this manneris shown in FIG. 17 .

Example 15: Mesalazine DR/IR Minitablets+DR/ER Minitablets

Mesalazine DR/IR minitablets prepared as described in Example 8 andDR/ER minitablets prepared as described in Example 12 are combined in a30:70 ratio. A release profile for the combination product is shown inFIG. 18 .

To prepare a pharmaceutical product, the combined DR/IR and DR/ERminitablets can be filled into a container, as illustrated in the bottomthird of FIG. 2 and FIG. 3 . To prepare a unit dose pharmaceuticalproduct, a unit dose of the combined DR/IR and DR/ER minitablets can befilled into a container.

Example 16: Mesalazine DR/IR Minitablets+Mesalazine DR/ER Minitablets

Mesalazine DR/IR minitablets prepared as described in Example 8 andDR/ER minitablets prepared as described in Example 12 are combined in a50:50 ratio. A dissolution profile for the combination product is shownin FIG. 19 .

To prepare a pharmaceutical product, the combined DR/IR and DR/ERminitablets can be filled into a container, as illustrated in the bottomthird of FIG. 2 and FIG. 3 . To prepare a unit dose pharmaceuticalproduct, a unit dose of the combined DR/IR and DR/ER minitablets can befilled into a container.

Example 17: Mesalazine DR/IR Minitablets+Mesalazine DR/ER Minitablets

Mesalazine DR/IR minitablets prepared as described in Example 8 andmesalazine DR/ER minitablets prepared as described in Example 13 arecombined in a 30:70 ratio. A release profile for the combination productis shown in FIG. 20 .

Example 18: DR/IR Minitablets+DR/ER Minitablets

DR/IR minitablets prepared as described in Example 8 and DR/ERminitablets prepared as described in Example 14 are combined in a 30:70ratio. A release profile for the combination product is shown in FIG. 21.

Example 19: Preparation of Combination Products

To provide a unit dose pharmaceutical product of nicotinamide andmesalazine, a unit dose of nicotinamide DR/IR and DR/ER minitablets anda unit dose of DR/IR and DR/ER mesalazine minitablets are filled into acontainer, such as a sachet, capsule or vial.

What is claimed is:
 1. A unit dose pharmaceutical product formulated fororal administration of nicotinamide to a subject, comprising: (a) aplurality of delayed-immediate release minitablets comprising acompressed matrix comprising nicotinamide provided with a pH-dependententeric coating, wherein the delayed-immediate release minitabletsselectively release nicotinamide at a pH of about 5.5 or greater in thedistal ileum; and (b) a plurality of delayed-extended releaseminitablets comprising a compressed matrix comprising nicotinamideprovided with an inner pH-independent extended release coating and anouter pH-dependent enteric coating, wherein the delayed-extended releaseminitablets selectively release nicotinamide at a pH of about 7 orgreater in the colon; optionally, wherein (a) and (b) are provided in asachet, capsule, or vial; wherein: the relative amounts of (a) and (b)in the unit dose pharmaceutical product are such that from 10 to 90% w/wof the nicotinamide provided in the unit dose pharmaceutical is presentin the delayed-extended release minitablets of (b); and the total amountof nicotinamide in the unit dose pharmaceutical product is from 0.25 to6 g.
 2. The unit dose pharmaceutical product of claim 1, wherein, whensubject to in vitro dissolution testing according to USP Type 1 Basketat 37° C. and 100 rpm in 500 mL dissolution medium of pH 1.2 buffer for2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 7 buffer,the delayed-immediate release minitablets exhibit release of less than10% of their total nicotinamide content at pH 1.2 and pH 4.5, andexhibit release of all of their total nicotinamide content within 60minutes at pH
 7. 3. The unit dose pharmaceutical product of any one ofclaim 1, wherein, when subject to in vitro dissolution testing accordingto USP Type 1 Basket at 37° C. and 100 rpm in 500 mL dissolution mediumof pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours,followed by pH 7 buffer, the delayed-immediate release minitabletsexhibit release of less than 10% of their total nicotinamide content atpH 1.2 and pH 4.5, and exhibit release of all of their totalnicotinamide content within 30 minutes at pH
 7. 4. The unit dosepharmaceutical product of claim 1, wherein the delayed-immediate releaseminitablets of (a) release at least 50% w/w of their total nicotinamidecontent in the distal ileum.
 5. The unit dose pharmaceutical product ofclaim 1, wherein the delayed-immediate release minitablets of (a)release at least 70% w/w of their total nicotinamide content in thedistal ileum.
 6. The unit dose pharmaceutical product of claim 1,wherein, when subject to in vitro dissolution testing according to USPType 1 Basket at 37° C. and 100 rpm in 500 mL dissolution medium of pH1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followedby pH 7.0 buffer for 12 hours, the delayed-extended release minitabletsexhibit no release of nicotinamide at pH 1.2 and pH 4.5, and exhibitextended release of nicotinamide over at least 4 hours at pH 7.0.
 7. Theunit dose pharmaceutical product of claim 1, wherein, when subject to invitro dissolution testing according to USP Type 1 Basket at 37° C. and100 rpm in 500 mL dissolution medium of pH 1.2 buffer for 2 hours,followed by pH 4.5 buffer for 2 hours, followed by pH 7.0 buffer for 12hours, the delayed-extended release minitablets exhibit no release ofnicotinamide at pH 1.2 and pH 4.5, and exhibit extended release ofnicotinamide over at least 8-12 hours at pH 7.0.
 8. The unit dosepharmaceutical product of claim 1, wherein the delayed-extended releaseminitablets of (b) release at least 50% w/w of their total nicotinamidecontent in the colon.
 9. The unit dose pharmaceutical product of claim1, wherein the delayed-extended release minitablets of (b) release atleast 70% w/w of their total nicotinamide content in the colon.
 10. Theunit dose pharmaceutical product of claim 1, wherein the compressedmatrix of (a) and the compressed matrix of (b) comprise at least 60% w/wnicotinamide and, optionally, one or more selected from apharmaceutically acceptable binder, a pharmaceutically acceptablefiller, and a pharmaceutically acceptable lubricant.
 11. The unit dosepharmaceutical product of claim 1, wherein: the compressed matrix of (a)and the compressed matrix of (b) each comprise nicotinamide,hydroxylpropyl cellulose, microcrystalline cellulose, and magnesiumstearate; the pH-dependent enteric coating of (a) comprises one or morepolymers selected from methacrylic acid and ethyl acrylate copolymer1:1, hypromellose acetate succinate, and hypromellose phthalate; thepH-dependent enteric coating of (b) comprises one or more polymersselected from the group consisting of methacrylic acid and methylmethacrylate copolymer 1:2, poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) [7:3:1] and hypromellose acetatesuccinate; the pH-independent extended release coating of (b) comprisesethyl cellulose and hydroxypropyl methylcellulose; and optionally, theminitablets of (a) and/or the minitablets of (b) further comprise a sealcoat exterior to the pH dependent enteric coating.
 12. The unit dosepharmaceutical product of claim 1, wherein the minitablets of (a) andthe minitablets of (b) have a longest diameter of 1-4 mm.
 13. A methodof administering nicotinamide to a subject in need thereof, or fortreating inflammatory bowel disease, comprising orally administering tothe subject a unit dose pharmaceutical product according to claim
 1. 14.A unit dose pharmaceutical product formulated for oral administration ofnicotinamide and mesalazine to a subject, comprising: (a) a plurality ofdelayed-immediate release minitablets comprising a compressed matrixcomprising nicotinamide provided with a pH-dependent enteric coating,wherein the delayed-immediate release minitablets selectively releasenicotinamide at a pH of about 5.5 or greater in the distal ileum; (b) aplurality of delayed-extended release minitablets comprising acompressed matrix comprising nicotinamide provided with an innerpH-independent extended release coating and an outer pH-dependententeric coating, wherein the delayed-extended release minitabletsselectively release nicotinamide at a pH of about 7 or greater in thecolon; (c) a plurality of delayed-immediate release minitabletscomprising a compressed matrix comprising mesalazine provided with apH-dependent enteric coating, wherein the delayed-immediate releaseminitablets selectively release mesalazine at a pH of about 5.5 orgreater in the distal ileum; and (d) a plurality of delayed-extendedrelease minitablets comprising a compressed matrix comprising mesalazineprovided with an inner pH-independent extended release coating and anouter pH-dependent enteric coating, wherein the delayed-extended releaseminitablets selectively release mesalazine at a pH of about 7 or greaterin the colon; wherein: the relative amounts of (a) and (b) in the unitdose pharmaceutical product are such that from 10 to 90% w/w of thenicotinamide provided in the unit dose pharmaceutical is present in thedelayed-extended release minitablets of (b); the relative amounts of (c)and (d) in the unit dose pharmaceutical product are such that from 10 to90% w/w of the mesalazine provided in the unit dose pharmaceutical ispresent in the delayed-extended release minitablets of (d); wherein therelative amounts of (a) and (b) may be selected independently of therelative amounts of (c) and (d) and the relative amounts of (c) and (d)may be selected independently of the relative amounts of (a) and (b);the total amount of nicotinamide in the unit dose pharmaceutical productis from 0.25 to 4 g, and the total amount of mesalazine in the unit dosepharmaceutical product is from 0.4 to 6 g.
 15. A method for orallyadministering nicotinamide and mesalazine to a subject in need thereof,or for treating inflammatory bowel disease, comprising orallyadministering a unit dose pharmaceutical product comprising nicotinamideand mesalazine minitablets according to claim
 14. 16. A method of makinga unit dose pharmaceutical product according to claim 1, comprising: (a)preparing a plurality of delayed-immediate release minitablets (a); (b)preparing a plurality of delayed-extended release minitablets (b); (c)providing (a) and (b) in a sachet, capsule, or vial, thereby obtainingthe unit dose pharmaceutical product, wherein: the relative amounts of(a) and (b) in the unit dose pharmaceutical product are such that from10 to 90% w/w of the nicotinamide provided in the unit dosepharmaceutical is present in the delayed-extended release minitablets of(b), and the total amount of nicotinamide in the unit dosepharmaceutical product is from 0.25 to 6 g.